BioPAX pathway converted from "Antiviral mechanism by IFN-stimulated genes" in the Reactome database.Antiviral mechanism by IFN-stimulated genesAntiviral mechanism by IFN-stimulated genesInterferons activate JAK–STAT signaling, which leads to the transcriptional induction of hundreds of IFN-stimulated genes (ISGs). The ISG-encoded proteins include direct effectors which inhibit viral infection through diverse mechanisms as well as factors that promote adaptive immune responses. The ISG proteins generated by IFN pathways plays key roles in the induction of innate and adaptive immune responses.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18ISG15 antiviral mechanismISG15 antiviral mechanismInterferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Interaction of ISG15 with NEDD4 and inhibition of Ebola virus buddingInteraction of ISG15 with NEDD4 and inhibition of Ebola virus buddingEbola virus VP40 virus-like particles (VLPs) requires the interaction of overlapping L-domains in the VP40 protein with host NEDD4 protein for efficient budding. Mono-ubiquitination of VP40 mediated by the NEDD4 E3 ligase is thought to be required for virus budding and release. ISG15 interacts with NEDD4 and inhibits the transfer of ubiquitin from the E2 enzyme to NEDD4. This prevents NEDD4-mediated ubiquitination of Ebola virus VP40 which is required for virion release.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 9759921cytosolGO0005829UniProt:P46934 NEDD4NEDD4NEDD4-1PIG53NEDD4KIAA0093FUNCTION E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates 'Lys-63' in target proteins (PubMed:23644597). Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).FUNCTION (Microbial infection) Involved in the ubiquitination of Ebola virus protein VP40 which plays a role in viral budding.ACTIVITY REGULATION Activated by NDFIP1- and NDFIP2-binding.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with UBE2D2. Binds SCNN1A, SCNN1B and SCNN1G. Binds, in vitro, through the WW2 and WW3 domains, to neural isoforms of ENAH that contain the PPSY motif. Interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, PMEPAI and PRRG2 (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity). Interaction with PTEN is questionable according to PubMed:18562292. Interacts (via C2 domain) with GRB10 (via SH2 domain). Interacts with ERBB4 (By similarity). Interacts with TNIK; the interaction is direct, allows the TNIK-dependent recruitment of RAP2A and its ubiquitination by NEDD4. Interacts (via WW3 domain) with TNK2; EGF promotes this interaction. Interacts (via WW3 domain) with FGFR1 (via C-terminus). Interacts with OTUD7B. Interacts with ISG15. Interacts (via WW domain) with RAPGEF2; this interaction leads to ubiquitination and degradation via the proteasome pathway. Interacts (via WW domains) with ARRDC3 (via PPXY motifs) (PubMed:20559325, PubMed:24379409). Interacts with LAPTM4B; may play a role in the lysosomal sorting of LAPTM4B (PubMed:22096579). Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3 (PubMed:21191027). Interacts with ZBTB7B (By similarity).SUBUNIT (Microbial infection) Interacts with viral proteins that contain a late-budding motif P-P-P-Y. This interaction is essential for viral particle budding of many retroviruses, like HTLV-1 Gag and MLV Gag. Interacts with Herpes simplex virus 2 (HHV-2) protein UL56; this interaction induces NEDD4 degradation (PubMed:18353951). Interacts with Ebola virus protein VP40 (PubMed:12559917).DOMAIN The WW domains mediate interaction with PPxY motif-containing proteins (PubMed:21191027). The WW domains mediate interaction with LITAF, RNF11, WBP1, WBP2, PMEPAI, NDFIP1 and PRRG2 (By similarity).PTM Auto-ubiquitinated.MISCELLANEOUS A cysteine residue is required for ubiquitin-thioester formation.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtP46934Chain Coordinates1EQUAL1319EQUALReactome DB_ID: 9365521UniProt:P05161 ISG15ISG15ISG15UCRPG1P2FUNCTION Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Can also isgylate: EIF2AK2/PKR which results in its activation, DDX58/RIG-I which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL (PubMed:29100055).SUBUNIT Homodimer; disulfide-linked (PubMed:2440890). Interacts with, and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (PubMed:11157743, PubMed:15131269). Interacts with NEDD4 (PubMed:18305167).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein E3.SUBUNIT (Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.TISSUE SPECIFICITY Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-cancerous tissue. In bladder cancer, the increase in expression exhibits a striking positive correlation with more advanced stages of the disease.INDUCTION Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses.DOMAIN Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein (PubMed:18356159).PTM S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.PTM Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases.UniProtP051612EQUAL157EQUALReactome DB_ID: 11693841ISG15:NEDD4 [cytosol]ISG15:NEDD4Reactome DB_ID: 97599211EQUAL1319EQUALReactome DB_ID: 93655212EQUAL157EQUALReactome Database ID Release 751169384Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169384ReactomeR-HSA-11693841Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169384.1Reactome Database ID Release 751169399Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169399ReactomeR-HSA-11693991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169399.1http://www.mdpi.com/1999-4915/2/10/2154/Antiviral Properties of ISG15Lenschow, DJ18305167Pubmed2008ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activityOkumura, APitha-Rowe, Paula MHarty, RNProc Natl Acad Sci U S A 105:3974-912525615Pubmed2003Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4Licata, JMSimpson-Holley, MWright, NTHan, ZParagas, JHarty, RNJ Virol 77:1812-920153823Pubmed2010ISG15 and immune diseasesJeon, YJYoo, HMChung, CHBiochim Biophys Acta 1802:485-9611095724Pubmed2000A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus buddingHarty, RNBrown, MEWang, GHuibregtse, JHayes, FPProc Natl Acad Sci U S A 97:13871-618287095Pubmed2008ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral responseMalakhova, OAZhang, DEJ Biol Chem 283:8783-76.3.2.19Activation of ISG15 by UBA7 E1 ligaseActivation of ISG15 by UBA7 E1 ligaseUbiquitin ligase UBE1L is the ISG15 activating enzyme. UBE1L activates ISG15 in an ATP-dependent process that links UBE1L to ISG15 via a thioester bond. Arginine 153 (R153) in human ISG15 is identified as the key residue for ISG15 and UBE1L's interaction.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 93655212EQUAL157EQUALReactome DB_ID: 1135921ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 9365501UniProt:P41226 UBA7UBA7UBA7UBE2UBE1LFUNCTION Activates ubiquitin by first adenylating with ATP its C-terminal glycine residue and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Catalyzes the ISGylation of influenza A virus NS1 protein.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Monomer (By similarity). Binds and is involved in the conjugation of G1P2/ISG15.TISSUE SPECIFICITY Expressed in a variety of normal and tumor cell types, but is reduced in lung cancer cell lines.PTM ISGylated.MISCELLANEOUS There are two active sites within the E1 molecule, allowing it to accommodate two ubiquitin moieties at a time, with a new ubiquitin forming an adenylate intermediate as the previous one is transferred to the thiol site.SIMILARITY Belongs to the ubiquitin-activating E1 family.UniProtP412261EQUAL1012EQUALReactome DB_ID: 11693901ISG15:UBA7 [cytosol]ISG15:UBA7ISG15:UBE1LActivated ISG15Reactome DB_ID: 93655212EQUAL157EQUALReactome DB_ID: 93655011EQUAL1012EQUALReactome Database ID Release 751169390Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169390ReactomeR-HSA-11693902Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169390.2Reactome DB_ID: 765771adenosine 5'-monophosphate [ChEBI:16027]adenosine 5'-monophosphateChEBI16027Reactome DB_ID: 1112941diphosphoric acid [ChEBI:29888]diphosphoric acidChEBI29888PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9365501EQUAL1012EQUALGO0004842GO molecular functionReactome Database ID Release 751169396Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169396Reactome Database ID Release 751169397Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169397ReactomeR-HSA-11693973Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169397.319073728Pubmed2009ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virusGiannakopoulos, NVArutyunova, ELai, CLenschow, DJHaas, ALVirgin, HWJ Virol 83:1602-1018583345Pubmed2008The basis for selective E1-E2 interactions in the ISG15 conjugation systemDurfee, LAKelley, MLHuibregtse, JMJ Biol Chem 283:23895-902Transfer of ISG15 from E1 to E2 (UBCH8)Transfer of ISG15 from E1 to E2 (UBCH8)Activated ISG15 linked to UBE1L is transferred to the E2 conjugating enzyme UBCH8.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 11693901Reactome DB_ID: 9360141UniProt:O14933 UBE2L6UBE2L6UBE2L6UBCH8FUNCTION Catalyzes the covalent attachment of ubiquitin or ISG15 to other proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Promotes ubiquitination and subsequent proteasomal degradation of FLT3.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with RNF19A, RNF19B and RNF144B. Interacts with FLT3 (tyrosine phosphorylated).TISSUE SPECIFICITY Present in natural killer cells (at protein level).INDUCTION By IFNB1/IFN-beta.PTM ISGylated.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.UniProtO149331EQUAL153EQUALReactome DB_ID: 11693851ISG15:UBCH8 [cytosol]ISG15:UBCH8Reactome DB_ID: 93601411EQUAL153EQUALReactome DB_ID: 93655212EQUAL157EQUALReactome Database ID Release 751169385Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169385ReactomeR-HSA-11693851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169385.1Reactome DB_ID: 93655011EQUAL1012EQUALPHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9360141EQUAL153EQUALGO0043130GO molecular functionReactome Database ID Release 751169400Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169400Reactome Database ID Release 751169404Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169404ReactomeR-HSA-11694042Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169404.215485925Pubmed2004Interferon-inducible ubiquitin E2, Ubc8, is a conjugating enzyme for protein ISGylationKim, KIGiannakopoulos, NVVirgin, HWZhang, DEMol Cell Biol 24:9592-60015131269Pubmed2004The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like proteinZhao, CBeaudenon, SLKelley, MLWaddell, MBYuan, WSchulman, BAHuibregtse, JMKrug, RMProc Natl Acad Sci U S A 101:7578-8211157743Pubmed2001Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 proteinYuan, WKrug, RMEMBO J 20:362-71Interaction of E3 ligase with ISG15:E2 complexInteraction of E3 ligase with ISG15:E2 complexUbiquitin ligase HERC5/CEB1 appears to be the predominant E3 ligase for ISGylation; EFP and HHARI/ARIH1 have also been reported as ISG15 E3 ligases. The E3 ligase recognizes specific target substrates and mediates the transfer of ISG15 from E2 to the substrate.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 11693851Converted from EntitySet in ReactomeReactome DB_ID: 11693811ISG15 E3 ligases [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityARIH1 [cytosol]HERC5 [cytosol]UniProtQ9Y4X5UniProtQ9UII4Reactome DB_ID: 11693831ISG15:UBCH8:ISG15 E3 ligase [cytosol]ISG15:UBCH8:ISG15 E3 ligaseReactome DB_ID: 11693851Converted from EntitySet in ReactomeReactome DB_ID: 11693811Reactome Database ID Release 751169383Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169383ReactomeR-HSA-11693831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169383.1Reactome Database ID Release 751169403Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169403ReactomeR-HSA-11694031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169403.117289916Pubmed2007ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHPOkumura, FZou, WZhang, DEGenes Dev 21:255-6016352599Pubmed2006The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligaseZou, WZhang, DEJ Biol Chem 281:3989-9416407192Pubmed2006Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cellsDastur, ABeaudenon, SKelley, MKrug, RMHuibregtse, JMJ Biol Chem 281:4334-816815975Pubmed2006HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targetsWong, JJPung, YFSze, NSChin, KCProc Natl Acad Sci U S A 103:10735-40ISGylation of protein translation regulator 4EHPISGylation of protein translation regulator 4EHP4EHP is a member of eukaryotic translation initiation factor 4E (eIF4E) family that acts as an mRNA 5' cap structure-binding protein and suppresses translation. 4EHP is one of the targets of ISG15 and ISGylated 4EHP has a much higher cap structure-binding activity.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 16788221UniProt:O60573 EIF4E2EIF4E2EIF4EL3EIF4E2FUNCTION Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation (PubMed:17368478, PubMed:25624349, PubMed:9582349). Acts as a repressor of translation initiation (PubMed:22751931). In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap (By similarity). In P-bodies, component of a complex that promotes miRNA-mediated translational repression (PubMed:28487484).SUBUNIT Interacts with EIF4EBP1, EIF4EBP2 and EIF4EBP3 (PubMed:15153109, PubMed:17368478). Does not interact with eIF4G (EIF4G1, EIF4G2 or EIF4G3) (By similarity). Component of the 4EHP-GYF2 complex, at least composed of EIF4E2, GIGYF2 and ZNF598 (PubMed:22751931). Interacts with GIGYF2 (via the 4EHP-binding motif); the interaction is direct (PubMed:22751931). Interacts with EIF4ENIF1/4E-T (via YXXXXLphi motif); increasing affinity for the 7-methylguanosine-containing mRNA cap (PubMed:23991149, PubMed:28487484).PTM Ubiquitinated by ARIH1 (PubMed:14623119, PubMed:25624349). The consequences of ubiquitination are however unclear: according to a report, EIF4E2 ubiquitination leads to promote EIF4E2 cap-binding and protein translation arrest (PubMed:25624349). According to another report ubiquitination leads to its subsequent degradation (PubMed:14623119).PTM ISGylation enhances its cap structure-binding activity and translation-inhibition activity.SIMILARITY Belongs to the eukaryotic initiation factor 4E family.UniProtO605731EQUAL245EQUALReactome DB_ID: 11693831Reactome DB_ID: 16788341ISGylated 4EHP [cytosol]ISGylated 4EHPReactome DB_ID: 167882211EQUAL245EQUALReactome DB_ID: 11693831Reactome Database ID Release 751678834Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678834ReactomeR-HSA-16788341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1678834.1Reactome Database ID Release 751678843Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678843ReactomeR-HSA-16788431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1678843.1Competitive inhibition of translation initiation by ISGylated 4EHPCompetitive inhibition of translation initiation by ISGylated 4EHPEukaryotic translation initiation factor 4F (eIF4F) is a protein complex that mediates recruitment of ribosomes to mRNA (Gingras et al. 1999). eIF4F contains complex of cap-binding protein eIF4E, scaffold protein eIF4G, and RNA helicase eIF4A. There are three eIF4E-family members in mammals termed eIF4E-1 (eIF4E), eIF4E2 (4EHP), and eIF4E3, of which both eIF4E and eIF4E3 are able to bind to eIF4G to facilitate translation initiation. However, 4EHP does not interact with eIF4G and thus cannot function in ribosome recruitment. 4EHP competes with eIF4E or eIF4E3 for binding to the RNA 5? cap structure and prevents translation initiation. ISGylated 4EHP has a much higher cap structure binding activity, suggesting a regulatory function of ISGylation in protein translation during immune responses (Okumura et al. 2007, Joshi et al. 2004).Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 16788341Reactome DB_ID: 725851eIF4F:mRNA [cytosol]eIF4F:mRNAReactome DB_ID: 16788321EIF4F [cytosol]EIF4FConverted from EntitySet in ReactomeReactome DB_ID: 16788291EIF4E1/EIF4E3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityEIF4E3 [cytosol]EIF4E [cytosol]UniProtQ8N5X7UniProtP06730Converted from EntitySet in ReactomeReactome DB_ID: 16788281EIF4G [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityEIF4G2 [cytosol]EIF4G1 [cytosol]EIF4G3 [cytosol]UniProtP78344UniProtQ04637UniProtO43432Converted from EntitySet in ReactomeReactome DB_ID: 4298421eIF4A [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityEIF4A2 [cytosol]EIF4A3 [cytosol]EIF4A1 [cytosol]UniProtQ14240UniProtP38919UniProtP60842Reactome Database ID Release 751678832Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678832ReactomeR-HSA-16788321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1678832.1Reactome DB_ID: 723231mRNA [cytosol]mRNAmessenger RNAReactome Database ID Release 7572585Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=72585ReactomeR-HSA-725851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-72585.1Reactome DB_ID: 16788361ISGylated 4EHP:mRNA [cytosol]ISGylated 4EHP:mRNAReactome DB_ID: 16788341Reactome DB_ID: 723231Reactome Database ID Release 751678836Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678836ReactomeR-HSA-16788361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1678836.1Reactome DB_ID: 16788321Reactome Database ID Release 751678842Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678842ReactomeR-HSA-16788421Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1678842.115153109Pubmed2004Characterization of mammalian eIF4E-family membersJoshi, BCameron, AJagus, REur J Biochem 271:2189-20310872469Pubmed1999eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translationGingras, ACRaught, BSonenberg, NAnnu Rev Biochem 68:913-636.3.2.19ISGylation of protein phosphatase 1 beta (PP2CB)ISGylation of protein phosphatase 1 beta (PP2CB)Protein phosphatase 1 beta (PPM1B/PP2CB) is a target for ISG15. PP2CB dephosphorylates TAK1 and suppresses TAK1/TAB1-mediated IkB alpha degradation and thereby controls the NF-kB signaling pathway, which plays a critical role in innate and adaptive immunity and cancer. ISGylation of PP2CB may block the suppressive function of the phosphatase against TAK1/TAB1 mediated NF-kB activation.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 1135921Reactome DB_ID: 11693751UniProt:O75688 PPM1BPPM1BPPM1BPP2CBFUNCTION Enzyme with a broad specificity. Dephosphorylates CDK2 and CDK6 in vitro. Dephosphorylates PRKAA1 and PRKAA2. Inhibits TBK1-mediated antiviral signaling by dephosphorylating it at 'Ser-172'. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB.SUBUNIT Monomer (By similarity). Interacts with PAK6. Interacts with the phosphorylated form of IKBKB/IKKB.TISSUE SPECIFICITY Highly expressed in heart and skeletal muscle.PTM Isgylation negatively regulates its activity.PTM N-myristoylation is essential for the recognition of its substrates for dephosphorylation.SIMILARITY Belongs to the PP2C family.UniProtO756881EQUAL479EQUALReactome DB_ID: 11693831Reactome DB_ID: 765771Reactome DB_ID: 11693911ISGylated PP2CB [cytosol]ISGylated PP2CBReactome DB_ID: 93655212EQUAL157EQUALReactome DB_ID: 116937511EQUAL479EQUALReactome Database ID Release 751169391Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169391ReactomeR-HSA-11693911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169391.1Reactome DB_ID: 93601411EQUAL153EQUALConverted from EntitySet in ReactomeReactome DB_ID: 11693811Reactome DB_ID: 1112941PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 1169383Reactome Database ID Release 751169401Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169401Reactome Database ID Release 751169405Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169405ReactomeR-HSA-11694051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169405.116872604Pubmed2006Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugationTakeuchi, TKobayashi, TTamura, SYokosawa, HFEBS Lett 580:4521-620946978Pubmed2010Emerging role of ISG15 in antiviral immunitySkaug, BChen, ZJCell 143:187-906.3.2.19ISGylation of host protein filamin BISGylation of host protein filamin BISG15 negatively regulates the scaffold protein filamin B. In response to type I IFNs, filamin B recruits RAC1, MEKK1, and MKK4, enhancing their sequential activation and thereby promoting JNK activation and apoptosis. ISGylation of filamin B leads to the disassociation of RAC1, MEKK1, and MKK4 from the scaffold, preventing type I IFN dependent JNK activation and apoptosis. It has been suggested that this inhibition of apoptosis may protect uninfected bystander cells from IFN-mediated apoptosis (Jeon et al, 2009).Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 1135921Reactome DB_ID: 3541631UniProt:O75369 FLNBFLNBTAPFLNBFLN3TABPFLN1LFUNCTION Connects cell membrane constituents to the actin cytoskeleton. May promote orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Various interactions and localizations of isoforms affect myotube morphology and myogenesis. Isoform 6 accelerates muscle differentiation in vitro.SUBUNIT Homodimer. Interacts with MICALL2 (By similarity). Interacts with RFLNA and RFLNB (By similarity). Isoform 1 interacts with FBLP1, FLNA, FLNC, GP1BA, INPPL1, ITGB1A, PSEN1 and PSEN2. Isoform 3 interacts with ITGB1A, ITGB1D, ITGB3 and ITGB6. Interacts with MYOT and MYOZ1. Interacts with HBV capsid protein.TISSUE SPECIFICITY Ubiquitous. Isoform 1 and isoform 2 are expressed in placenta, bone marrow, brain, umbilical vein endothelial cells (HUVEC), retina and skeletal muscle. Isoform 1 is predominantly expressed in prostate, uterus, liver, thyroid, stomach, lymph node, small intestine, spleen, skeletal muscle, kidney, placenta, pancreas, heart, lung, platelets, endothelial cells, megakaryocytic and erythroleukemic cell lines. Isoform 2 is predominantly expressed in spinal cord, platelet and Daudi cells. Also expressed in thyroid adenoma, neurofibrillary tangles (NFT), senile plaques in the hippocampus and cerebral cortex in Alzheimer disease (AD). Isoform 3 and isoform 6 are expressed predominantly in lung, heart, skeletal muscle, testis, spleen, thymus and leukocytes. Isoform 4 and isoform 5 are expressed in heart.DOMAIN Comprised of a NH2-terminal actin-binding domain, 24 internally homologous repeats and two hinge regions. Repeat 24 and the second hinge domain are important for dimer formation. The first hinge region prevents binding to ITGA and ITGB subunits.PTM ISGylation prevents ability to interact with the upstream activators of the JNK cascade and inhibits IFNA-induced JNK signaling.PTM Ubiquitination by a SCF-like complex containing ASB2 isoform 2 leads to proteasomal degradation which promotes muscle differentiation.DISEASE Interaction with FLNA may compensate for dysfunctional FLNA homodimer in the periventricular nodular heterotopia (PVNH) disorder.SIMILARITY Belongs to the filamin family.UniProtO753691EQUAL2602EQUALReactome DB_ID: 11693831Reactome DB_ID: 765771Reactome DB_ID: 11693881ISGylated Filamin B [cytosol]ISGylated Filamin BReactome DB_ID: 93655212EQUAL157EQUALReactome DB_ID: 35416311EQUAL2602EQUALReactome Database ID Release 751169388Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169388ReactomeR-HSA-11693881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169388.1Reactome DB_ID: 93601411EQUAL153EQUALConverted from EntitySet in ReactomeReactome DB_ID: 11693811Reactome DB_ID: 1112941PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 1169383Reactome Database ID Release 751169398Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169398ReactomeR-HSA-11693981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169398.112582176Pubmed2003High-throughput immunoblotting. Ubiquitiin-like protein ISG15 modifies key regulators of signal transductionMalakhov, MPKim, KIMalakhova, OAJacobs, BSBorden, ECZhang, DEJ Biol Chem 278:16608-1319270716Pubmed2009ISG15 modification of filamin B negatively regulates the type I interferon-induced JNK signalling pathwayJeon, YJChoi, JSLee, JYYu, KRKim, SMKa, SHOh, KHKim, KIZhang, DEBang, OSChung, CHEMBO Rep 10:374-8016009940Pubmed2005Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathwaysZhao, CDenison, CHuibregtse, JMGygi, SKrug, RMProc Natl Acad Sci U S A 102:10200-56.3.2.19ISGylation of E2 conjugating enzymesISGylation of E2 conjugating enzymesUbiquitin conjugating E2 enzymes UBC13 and UBCH6 are targets for ISGylation. This suppresses the ubiquitin-conjugating activity of both UBC13 and UBCH6. This modification may play an important role in the control of signal transduction pathways, such as the NF-kB pathway, which are associated with K63-linked polyubiquitination (Takeuchi et al, 2005).Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Converted from EntitySet in ReactomeReactome DB_ID: 11693781E2 congugating enzymes [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBE2E1 [cytosol]UBE2N [cytosol]UniProtP51965UniProtP61088Reactome DB_ID: 1135921Reactome DB_ID: 11693831Reactome DB_ID: 765771Reactome DB_ID: 93601411EQUAL153EQUALReactome DB_ID: 11693821ISGylated E2 conjugating enzymes [cytosol]ISGylated E2 conjugating enzymesConverted from EntitySet in ReactomeReactome DB_ID: 11693781Reactome DB_ID: 93655212EQUAL157EQUALReactome Database ID Release 751169382Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169382ReactomeR-HSA-11693821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169382.1Converted from EntitySet in ReactomeReactome DB_ID: 11693811Reactome DB_ID: 1112941PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 1169383Reactome Database ID Release 751169402Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169402ReactomeR-HSA-11694021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169402.116112642Pubmed2005ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activityTakeuchi, TYokosawa, HBiochem Biophys Res Commun 336:9-1316122702Pubmed2005ISG15 modification of ubiquitin E2 Ubc13 disrupts its ability to form thioester bond with ubiquitinZou, WPapov, VMalakhova, OKim, KIDao, CLi, JZhang, DEBiochem Biophys Res Commun 336:61-816428300Pubmed2005Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzymeTakeuchi, TIwahara, SSaeki, YSasajima, HYokosawa, HJ Biochem 138:711-96.3.2.19ISGylation of host proteinsISGylation of host proteinsMany host proteins are targets for ISGylation including constitutively expressed proteins involved in various cellular pathways such as immunity, RNA splicing, chromatin remodeling/polymerase II transcription, stress responses and translation. Many ISG15 target proteins are IFN alpha/beta-induced antiviral proteins such as PKR, MxA, IRF3, and RIG-I, also included are several key regulators of signal transduction such as PLC gamma1, JAK1, STAT1 and ERK1. The contribution of most of these modified proteins to antiviral activity is unclear because the fate of the vast majority of ISGylated target proteins is unknown.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Converted from EntitySet in ReactomeReactome DB_ID: 11693791ISG15 targets [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBE2E1 [cytosol]STAT1 [cytosol]MAPK3 [cytosol]JAK1 [cytosol]PLCG1 [cytosol]IFIT1 [cytosol]UniProtP42224UniProtP27361UniProtP23458UniProtP19174UniProtP09914Reactome DB_ID: 1135921Reactome DB_ID: 11693831Reactome DB_ID: 765771Reactome DB_ID: 11693871ISGylated host proteins [cytosol]ISGylated host proteinsConverted from EntitySet in ReactomeReactome DB_ID: 11693791Reactome DB_ID: 93655212EQUAL157EQUALReactome Database ID Release 751169387Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169387ReactomeR-HSA-11693871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169387.1Reactome DB_ID: 93601411EQUAL153EQUALConverted from EntitySet in ReactomeReactome DB_ID: 11693811Reactome DB_ID: 1112941PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 1169383Reactome Database ID Release 751169406Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169406ReactomeR-HSA-11694061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169406.116139798Pubmed2005Proteomic identification of proteins conjugated to ISG15 in mouse and human cellsGiannakopoulos, NVLuo, JKPapov, VZou, WLenschow, DJJacobs, BSBorden, ECLi, JVirgin, HWZhang, DEBiochem Biophys Res Commun 336:496-5066.3.2.19ISGylation of IRF3ISGylation of IRF3The transcription factor IRF3 is a target for ISGylation. Conjugation of ISG15 positively regulates IRF3 and thereby promotes induction of type I interferons. ISGylation of IRF3 prevents the binding of PIN1, a protein that promotes IRF3 ubiquitination and subsequent degradation.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 1662511UniProt:Q14653 IRF3IRF3IRF3FUNCTION Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses (PubMed:22394562, PubMed:25636800, PubMed:27302953). Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters (PubMed:11846977, PubMed:16846591, PubMed:16979567, PubMed:20049431). Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction (PubMed:16846591, PubMed:16979567, PubMed:20049431). Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases (PubMed:22394562, PubMed:25636800, PubMed:27302953). This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes (PubMed:16154084, PubMed:27302953). Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages (PubMed:16846591).ACTIVITY REGULATION In the absence of viral infection, maintained as a monomer in an autoinhibited state (PubMed:16846591, PubMed:16979567, PubMed:20049431). Phosphorylation by TBK1 and IKBKE disrupts this autoinhibition leading to the liberation of the DNA-binding and dimerization activities and its nuclear localization where it can activate type I IFN and ISG genes (PubMed:25636800). Phosphorylation and activation follow the following steps: innate adapter protein MAVS, STING1 or TICAM1 are first activated by viral RNA, cytosolic DNA and bacterial lipopolysaccharide (LPS), respectively, leading to activation of the kinases TBK1 and IKBKE (PubMed:25636800). These kinases then phosphorylate the adapter proteins on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25636800, PubMed:27302953).SUBUNIT Monomer (PubMed:16846591, PubMed:16979567, PubMed:20049431). Homodimer; phosphorylation-induced (PubMed:22394562, PubMed:25636800, PubMed:26347139). Interacts (when phosphorylated) with CREBBP (PubMed:16154084, PubMed:27302953). Interacts with MAVS (via phosphorylated pLxIS motif) (PubMed:16153868, PubMed:25636800, PubMed:27302953). Interacts with TICAM1 (via phosphorylated pLxIS motif) (PubMed:12471095, PubMed:14739303, PubMed:25636800, PubMed:27302953). Interacts with STING1 (via phosphorylated pLxIS motif) (PubMed:22394562, PubMed:28331227, PubMed:25636800, PubMed:27302953). Interacts with IKBKE and TBK1 (PubMed:16281057, PubMed:23478265, PubMed:25636800). Interacts with TICAM2 (PubMed:14517278). Interacts with RBCK1 (PubMed:18711448). Interacts with HERC5 (PubMed:20308324). Interacts with DDX3X (phosphorylated at 'Ser-102'); the interaction allows the phosphorylation and activation of IRF3 by IKBKE (PubMed:23478265, PubMed:27980081). Interacts with TRIM21 and ULK1, in the presence of TRIM21; this interaction leads to IRF3 degradation by autophagy (PubMed:18641315, PubMed:26347139). Interacts with RIOK3; RIOK3 probably mediates the interaction of TBK1 with IRF3 (PubMed:19557502). Interacts with ILRUN; the interaction inhibits IRF3 binding to its DNA consensus sequence (PubMed:29802199). Interacts with LYAR; this interaction impairs IRF3 DNA-binding activity (PubMed:31413131). Interacts with TRAF3 (PubMed:27980081). Interacts with ZDHHC11; ZDHHC11 recruits IRF3 to STING1 upon DNA virus infection and thereby promotes IRF3 activation (PubMed:28331227).SUBUNIT (Microbial infection) Interacts with rotavirus A NSP1 (via pLxIS motif); this interaction leads to the proteasome-dependent degradation of IRF3.SUBUNIT (Microbial infection) Interacts with herpes virus 8/HHV-8 protein VIRF1 (PubMed:11314014).SUBUNIT (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction is involved in the suppression of IRF3 expression and phosphorylation by the virus.TISSUE SPECIFICITY Expressed constitutively in a variety of tissues.PTM Constitutively phosphorylated on many Ser/Thr residues (PubMed:22394562, PubMed:23478265, PubMed:23746807). Activated following phosphorylation by TBK1 and IKBKE (PubMed:23478265, PubMed:23746807, PubMed:25636800). Innate adapter protein MAVS, STING1 or TICAM1 are first activated by viral RNA, cytosolic DNA, and bacterial lipopolysaccharide (LPS), respectively, leading to activation of the kinases TBK1 and IKBKE (PubMed:25636800). These kinases then phosphorylate the adapter proteins on the pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs (PubMed:25636800).PTM (Microbial infection) Phosphorylation and subsequent activation of IRF3 is inhibited by vaccinia virus protein E3.PTM Ubiquitinated; ubiquitination involves RBCK1 leading to proteasomal degradation. Polyubiquitinated; ubiquitination involves TRIM21 leading to proteasomal degradation.PTM ISGylated by HERC5 resulting in sustained IRF3 activation and in the inhibition of IRF3 ubiquitination by disrupting PIN1 binding. The phosphorylation state of IRF3 does not alter ISGylation.SIMILARITY Belongs to the IRF family.UniProtQ146531EQUAL427EQUALReactome DB_ID: 1135921Reactome DB_ID: 11693831Reactome DB_ID: 765771Reactome DB_ID: 93601411EQUAL153EQUALConverted from EntitySet in ReactomeReactome DB_ID: 11693811Reactome DB_ID: 1112941Reactome DB_ID: 11693891ISGylated IRF3 [cytosol]ISGylated IRF3Reactome DB_ID: 93655212EQUAL157EQUALReactome DB_ID: 16625111EQUAL427EQUALReactome Database ID Release 751169389Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169389ReactomeR-HSA-11693891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169389.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 1169383Reactome Database ID Release 751169394Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169394ReactomeR-HSA-11693941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169394.120308324Pubmed2010Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modificationShi, HXYang, KLiu, XLiu, XYWei, BShan, YFZhu, LHWang, CMol Cell Biol 30:2424-3616914094Pubmed2006ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradationLu, GReinert, JTPitha-Rowe, IOkumura, AKellum, MKnobeloch, KPHassel, BPitha-Rowe, Paula MCell Mol Biol (Noisy-le-grand) 52:29-41PIN1 mediated IRF3 degradationPIN1 mediated IRF3 degradationPIN1 acts as a negative regulator of IFN induction. Its association with IRF3 leads to ubiquitin-mediated proteosomal degradation of IRF3. PIN1 on its own does not have ubiquitin activation, transfer or ligase activities. Exactly how this IRF3 degradation is achieved is unclear at present. Immunoprecipitation of ubiquitin followed by immunoblot analysis for IRF3 demonstrated that polyubiquitination of IRF3 was induced by RNA stimulation and that polyubiquitination was augmented by PIN1 expression and abrogated by expression of PIN1-specific shRNA.Authored: Garapati, P V, 2010-08-02Reviewed: Kawai, T, Akira, S, 2010-10-30Edited: Garapati, P V, 2010-08-22Reactome DB_ID: 9364441nucleoplasmGO0005654p-IRF3 dimer:PIN1 [nucleoplasm]p-IRF3 dimer:PIN1Reactome DB_ID: 9360161UniProt:Q13526 PIN1PIN1PIN1FUNCTION Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs. By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes (PubMed:21497122, PubMed:22033920, Ref. 21). Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:23623683, PubMed:27561354).SUBUNIT Interacts with STIL. Interacts with KIF20B. Interacts with NEK6. Interacts (via WW domain) with PRKX. Interacts with BTK. Interacts (via PpiC domain) with DAPK1. Interacts with the phosphorylated form of RAF1. Interacts (via WW domain) with ATCAY; upon NGF stimulation. Interacts with PML (isoform PML-4) and BCL-6. Interacts with FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Directly interacts with RBBP8/CtIP; this interaction depends upon RBBP8 phosphorylation (PubMed:23623683).TISSUE SPECIFICITY The phosphorylated form at Ser-71 is expressed in normal breast tissue cells but not in breast cancer cells.DOMAIN The WW domain is required for the interaction with STIL and KIF20B.PTM Phosphorylation at Ser-71 by DAPK1 results in inhibition of its catalytic activity, nuclear localization, and its ability to induce centrosome amplification, chromosome instability and cell transformation.UniProtQ135261EQUAL163EQUALReactome DB_ID: 9364461p-IRF3:p-IRF3 [nucleoplasm]p-IRF3:p-IRF3Reactome DB_ID: 9364182O-phospho-L-serine at 396396EQUALO-phospho-L-serine [MOD:00046]O-phospho-L-serine at 398398EQUALO-phospho-L-serine at 402402EQUALO-phospho-L-serine at 405405EQUALO-phospho-L-threonine at 404404EQUALO-phospho-L-threonine [MOD:00047]O-phospho-L-serine at 339339EQUAL1EQUAL427EQUALReactome Database ID Release 75936446Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=936446ReactomeR-HSA-9364461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-936446.1Reactome Database ID Release 75936444Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=936444ReactomeR-HSA-9364441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-936444.1Reactome DB_ID: 93601611EQUAL163EQUALPHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 5244779unknown ligase [nucleoplasm]unknown ligaseGO0061630GO molecular functionReactome Database ID Release 75936422Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=936422Reactome Database ID Release 75936462Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=936462ReactomeR-HSA-9364623Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-936462.316699525Pubmed2006Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1Saitoh, TTun-Kyi, ARyo, AYamamoto, MFinn, GFujita, TAkira, ShizuoYamamoto, NLu, KPYamaoka, SNat Immunol 7:598-60519125153Pubmed2009Inhibition of IRF3-dependent antiviral responses by cellular and viral proteinsTsuchida, TKawai, TAkira, ShizuoCell Res 19:3-416715065Pubmed2006Pin-ning down immune responses to RNA virusesGoutagny, NSevera, MFitzgerald, Katherine ANat Immunol 7:555-7INHIBITIONThe transcription factor IRF3 is a target for ISGylation. Conjugation of ISG15 positively regulates IRF3 and thereby promotes induction of type I interferons. ISGylation of IRF3 prevents the binding of PIN1, a protein that promotes IRF3 ubiquitination and subsequent degradation.Reactome Database ID Release 751176076Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1176076ReactomeR-HSA-11760761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1176076.1Reactome DB_ID: 11693896.3.2.19ISGylation of viral protein NS1ISGylation of viral protein NS1Some viral proteins are also targeted for ISGylation. The well studied viral protein ISGylation is the modification of the influenza A viral protein NS1, which functions as an IFN antagonist during viral infection. Studies identified seven lysine residues in NS1 as potential ISGylation sites among which K41 (Zhao et al. 2010), K126 and K217 (Tang et al. 2010) were found to be critical. ISGylation at these sites disrupts NS1 association with importin-alpha, a protein required for the nuclear import of NS1.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 1691431NS1 dimer [cytosol]NS1 dimerReactome DB_ID: 1691182UniProt:P03496 NSNSNSFUNCTION Prevents the establishment of the cellular antiviral state by inhibiting TRIM25-mediated DDX58 ubiquitination, which normally triggers the antiviral transduction signal that leads to the activation of type I IFN genes by transcription factors IRF3 and IRF7. Prevents human EIF2AK2/PKR activation, either by binding double-strand RNA, or by interacting directly with EIF2AK2/PKR. This function may be important at the very beginning of the infection, when NS1 is mainly present in the cytoplasm. Also binds poly(A) and U6 snRNA.FUNCTION Inhibits post-transcriptional processing of cellular pre-mRNA, by binding and inhibiting two cellular proteins that are required for the 3'-end processing of cellular pre-mRNAs: the 30 kDa cleavage and polyadenylation specificity factor/CPSF4 and the poly(A)-binding protein 2/PABPN1. In turn, unprocessed 3' end pre-mRNAs accumulate in the host nucleus and are no longer exported to the cytoplasm. Cellular protein synthesis is thereby shut off very early after virus infection. Viral protein synthesis is not affected by the inhibition of the cellular 3' end processing machinery because the poly(A) tails of viral mRNAs are produced by the viral polymerase through a stuttering mechanism.SUBUNIT Homodimer. Interacts with host TRIM25 (via coiled coil); this interaction specifically inhibits TRIM25 multimerization and TRIM25-mediated DDX58 CARD ubiquitination. Interacts with human EIF2AK2/PKR, CPSF4, IVNS1ABP and PABPN1.DOMAIN The dsRNA-binding region is required for suppression of RNA silencing.PTM Upon interferon induction, ISGylated via host HERC5; this results in the impairment of NS1 interaction with RNA targets due to its inability to form homodimers and to interact with host EIF2AK2/PKR. There are two ISGylated forms: one form is ISGylated at Lys-20, Lys-41, Lys-217, and Lys-219, and another one at Lys-108, Lys-110, and Lys-126, they represent band I and II respectively. Lys-126 and Lys-217 are critical for host antiviral response in vivo.SIMILARITY Belongs to the influenza A viruses NS1 family.Influenza A virusNCBI Taxonomy11320UniProtP03496Reactome Database ID Release 75169143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=169143ReactomeR-FLU-1691434Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-FLU-169143.4Reactome DB_ID: 1135921Reactome DB_ID: 11693831Reactome DB_ID: 765771Reactome DB_ID: 11693921ISGylated NS1 [cytosol]ISGylated NS1Reactome DB_ID: 1691431Reactome DB_ID: 93655212EQUAL157EQUALReactome Database ID Release 751169392Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169392ReactomeR-HSA-11693923Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169392.3Reactome DB_ID: 93601411EQUAL153EQUALConverted from EntitySet in ReactomeReactome DB_ID: 11693811Reactome DB_ID: 1112941PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 1169383Reactome Database ID Release 751169395Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169395ReactomeR-HSA-11693953Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169395.320385878Pubmed2010Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1 proteinTang, YZhong, GZhu, LijunLiu, XShan, YFeng, HBu, ZChen, HWang, CJ Immunol 184:5777-9020133869Pubmed2010ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cellsZhao, CHsiang, TYKuo, RLKrug, RMProc Natl Acad Sci U S A 107:2253-820219937Pubmed2010Species-specific antagonism of host ISGylation by the influenza B virus NS1 proteinVersteeg, GAHale, BGvan Boheemen, SWolff, TLenschow, DJGarcia-Sastre, AJ Virol 84:5423-30Translocation of Influenza A virus nonstructural protein 1 (NS1A) into the nucleusTranslocation of Influenza A virus nonstructural protein 1 (NS1A) into the nucleusInfluenza A virus nonstructural protein 1 (NS1A) is a multifunctional protein that exists as a dimer and is involved in the inhibition of host cell antiviral pre-mRNA processing and counteracts host cell antiviral responses. Unlike most other RNA viruses, influenza viruses replicate in the nucleus of the host cells. NS1A protein carries two nuclear localization signal (NLS) elements and these sequence elements are recognized by importin-alpha/beta. In the cytoplasm NS1A binds to importin-alpha/beta and these protein complexes are then translocated into the nucleus through the nuclear pore complex (NPC). Note:Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red.Authored: Gillespie, ME, 2013-11-18Reviewed: Gale M, Jr, 2004-05-12 19:00:00Edited: Gillespie, ME, 2013-11-18Reactome DB_ID: 1691431Converted from EntitySet in ReactomeReactome DB_ID: 11760601Importin [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityKPNA2 [cytosol]KPNA7 [cytosol]KPNA4 [cytosol]KPNB1 [cytosol]KPNA3 [cytosol]KPNA1 [cytosol]KPNA5 [cytosol]UniProtP52292UniProtA9QM74UniProtO00629UniProtQ14974UniProtO00505UniProtP52294UniProtO15131Reactome DB_ID: 11760671NS1 homodimer:Importin [nucleoplasm]NS1 homodimer:ImportinConverted from EntitySet in ReactomeReactome DB_ID: 11760731Importin [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityKPNB1 [nucleoplasm]KPNA3 [nucleoplasm]KPNA2 [nucleoplasm]KPNA1 [nucleoplasm]KPNA4 [nucleoplasm]KPNA7 [nucleoplasm]KPNA5 [nucleoplasm]Reactome DB_ID: 1691451NS1 Homodimer [nucleoplasm]NS1 HomodimerReactome DB_ID: 1691132Reactome Database ID Release 75169145Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=169145ReactomeR-FLU-1691452Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-FLU-169145.2Reactome Database ID Release 751176067Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1176067ReactomeR-HSA-11760674Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1176067.4PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 157689nuclear envelopeGO0005635Nuclear Pore Complex (NPC) [nuclear envelope]Nuclear Pore Complex (NPC)Reactome DB_ID: 15775216UniProt:Q5SRE5 NUP188NUP188NUP188KIAA0169FUNCTION May function as a component of the nuclear pore complex (NPC).DISEASE Copy number variations of NUP188 gene may be a cause of heterotaxy, a congenital heart disease resulting from abnormalities in left-right (LR) body patterning.UniProtQ5SRE52EQUAL1749EQUALReactome DB_ID: 963418332Nup93 complex [nuclear envelope]Nup93 complexReactome DB_ID: 1576901UniProt:O75694 NUP155NUP155NUP155KIAA0791FUNCTION Essential component of nuclear pore complex. Could be essessential for embryogenesis. Nucleoporins may be involved both in binding and translocating proteins during nucleocytoplasmic transport.SUBUNIT Interacts with GLE1. Able to form a heterotrimer with GLE1 and NUP42 in vitro. Forms a complex with NUP35, NUP93, NUP205 and lamin B.TISSUE SPECIFICITY Expressed in all tissues tested, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.PTM Phosphorylated. Phosphorylation and dephosphorylation may be important for the function of NUP155 and may play a role in the reversible disassembly of the nuclear pore complex during mitosis (By similarity).PTM Disulfide-linked to NUP62. The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC (By similarity).SIMILARITY Belongs to the non-repetitive/WGA-negative nucleoporin family.UniProtO756941EQUAL1391EQUALReactome DB_ID: 1577491UniProt:Q8N1F7 NUP93NUP93NUP93KIAA0095FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:9348540). May anchor nucleoporins, but not NUP153 and TPR, to the NPC. During renal development, regulates podocyte migration and proliferation through SMAD4 signaling (PubMed:26878725).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:9348540, PubMed:15229283, PubMed:15703211). Component of the p62 complex, a complex composed of NUP62 and NUP54 (PubMed:9348540). Forms a complex with NUP35, NUP155, NUP205 and lamin B; the interaction with NUP35 is direct (PubMed:15703211). Does not interact with TPR (PubMed:12802065, PubMed:15229283). Interacts with SMAD4 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725).SUBUNIT (Microbial infection) Interacts with SARS-CoV translation inhibitor nsp1; this interaction may disrupt nuclear pore function.SIMILARITY Belongs to the nucleoporin interacting component (NIC) family.UniProtQ8N1F71EQUAL819EQUALReactome DB_ID: 1577481UniProt:Q8NFH5 NUP35NUP35NUP53MP44NUP35FUNCTION Functions as a component of the nuclear pore complex (NPC). NPC components, collectively referred to as nucleoporins (NUPs), can play the role of both NPC structural components and of docking or interaction partners for transiently associated nuclear transport factors. May play a role in the association of MAD1 with the NPC.SUBUNIT Interacts with TMEM48/NDC1. Forms a complex with NUP93, NUP155, NUP205 and lamin B; the interaction with NUP93 is direct.SIMILARITY Belongs to the Nup35 family.UniProtQ8NFH51EQUAL326EQUALReactome DB_ID: 1577541UniProt:Q92621 NUP205NUP205NUP205KIAA0225C7orf14FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:9348540). May anchor NUP62 and other nucleoporins, but not NUP153 and TPR, to the NPC (PubMed:15229283).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:9348540, PubMed:15229283). Forms a complex with NUP35, NUP93, NUP155 and lamin B (PubMed:15703211, PubMed:26878725). Does not interact with TPR (PubMed:12802065).SIMILARITY Belongs to the NUP186/NUP192/NUP205 family.UniProtQ926212EQUAL2012EQUALReactome Database ID Release 759634183Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9634183ReactomeR-HSA-96341831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9634183.1Reactome DB_ID: 1577038UniProt:P49792 RANBP2RANBP2RANBP2NUP358FUNCTION E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I (PubMed:11792325, PubMed:12032081, PubMed:15378033, PubMed:22194619, PubMed:15931224). Involved in transport factor (Ran-GTP, karyopherin)-mediated protein import via the F-G repeat-containing domain which acts as a docking site for substrates (PubMed:7775481). Binds single-stranded RNA (in vitro) (PubMed:7775481). May bind DNA (PubMed:7775481). Component of the nuclear export pathway (PubMed:10078529). Specific docking site for the nuclear export factor exportin-1 (PubMed:10078529). Sumoylates PML at 'Lys-490' which is essential for the proper assembly of PML-NB (PubMed:22155184). Recruits BICD2 to the nuclear envelope and cytoplasmic stacks of nuclear pore complex known as annulate lamellae during G2 phase of cell cycle (PubMed:20386726). Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity (PubMed:20676357, PubMed:23353830).PATHWAY Protein modification; protein sumoylation.SUBUNIT Part of the nuclear pore complex (PubMed:11839768, PubMed:20386726, PubMed:23353830, PubMed:7603572). Forms a complex with NXT1, NXF1 and RANGAP1 (PubMed:14729961). Forms a tight complex with RANBP1 and UBE2I (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with SUMO1 but not SUMO2 (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with PRKN (PubMed:16332688). Interacts with sumoylated RANGAP1 (PubMed:15378033, PubMed:10078529, PubMed:15826666). Interacts with CDCA8 (PubMed:19413330). Interacts with PML (isoform PML-4) (PubMed:22155184). Interacts with BICD2 (PubMed:20386726). Interacts with MCM3AP isoform GANP (PubMed:20005110).DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.DOMAIN The PPIase cyclophilin-type domain has high structural similarity with PPIA, but has extremely low and barely detectable proline isomerase activity (in vitro) (PubMed:23353830). Only about half of the residues that surround the PPIA active site cleft are conserved.PTM Polyubiquitinated by PRKN, which leads to proteasomal degradation.PTM The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC.DISEASE A chromosomal aberration involving RANBP2 is a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(2;8)(q12;p11) with FGFR1. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia.SIMILARITY Belongs to the RanBP2 E3 ligase family.CAUTION Despite the presence of a PPIase cyclophilin-type domain, it has probably no peptidyl-prolyl cis-trans isomerase activity.UniProtP497921EQUAL3224EQUALReactome DB_ID: 37788332Nup107-160 complex [cytosol]Nup107-160 complexReactome DB_ID: 3762431UniProt:Q8NFH3 NUP43NUP43NUP43FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13.UniProtQ8NFH31EQUAL380EQUALReactome DB_ID: 3762381UniProt:Q9BW27 NUP85NUP85NUP75NUP85PCNT1FUNCTION Essential component of the nuclear pore complex (NPC) that seems to be required for NPC assembly and maintenance (PubMed:12718872). As part of the NPC Nup107-160 subcomplex plays a role in RNA export and in tethering NUP96/Nup98 and NUP153 to the nucleus (PubMed:12718872). The Nup107-160 complex seems to be required for spindle assembly during mitosis (PubMed:16807356). NUP85 is required for membrane clustering of CCL2-activated CCR2 (PubMed:15995708). Seems to be involved in CCR2-mediated chemotaxis of monocytes and may link activated CCR2 to the phosphatidyl-inositol 3-kinase-Rac-lammellipodium protrusion cascade (PubMed:15995708). Involved in nephrogenesis (PubMed:30179222).SUBUNIT Component of the nuclear pore complex (NPC) (PubMed:12196509). Component of the NPC Nup107-160 subcomplex, consisting of at least NUP107, NUP98/Nup96, NUP160, NUP133, NUP85, NUP37, NUP43 and SEC13 (PubMed:15146057). Interacts with NUP160, NUP133 and SEC13 (PubMed:12718872, PubMed:30179222). Interacts with NUP37, NUP107 and NUP43 (PubMed:15146057). Interacts with CCR2 (PubMed:15995708).SIMILARITY Belongs to the nucleoporin Nup85 family.UniProtQ9BW271EQUAL656EQUALReactome DB_ID: 2039811UniProt:P55735 SEC13SEC13SEC13SEC13L1SEC13RSEC13AD3S1231EFUNCTION Functions as a component of the nuclear pore complex (NPC) and the COPII coat. At the endoplasmic reticulum, SEC13 is involved in the biogenesis of COPII-coated vesicles (PubMed:8972206). Required for the exit of adipsin (CFD/ADN), an adipocyte-secreted protein from the endoplasmic reticulum (By similarity).FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT At the nuclear pore: component of the Y-shaped Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. At the COPII coat complex: interacts with SEC31A and SEC31B. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:14517296, PubMed:16495487, PubMed:16957052, PubMed:18160040, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612). Interacts with SEC16A (PubMed:17428803, PubMed:19638414, PubMed:25201882). Interacts with SEC16B (PubMed:22355596).SIMILARITY Belongs to the WD repeat SEC13 family.UniProtP557352EQUAL322EQUALReactome DB_ID: 3762411UniProt:P57740 NUP107NUP107NUP107FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:12552102, PubMed:15229283, PubMed:30179222). Required for the assembly of peripheral proteins into the NPC (PubMed:15229283, PubMed:12552102). May anchor NUP62 to the NPC (PubMed:15229283). Involved in nephrogenesis (PubMed:30179222).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:12802065, PubMed:15229283, PubMed:26411495). Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and Nup96; this complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705, PubMed:26411495, PubMed:30179222). Does not interact with TPR (PubMed:12802065). Interacts with ZNF106 (By similarity).TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.SIMILARITY Belongs to the nucleoporin Nup84/Nup107 family.UniProtP577401EQUAL925EQUALReactome DB_ID: 3762531UniProt:Q12769 NUP160NUP160KIAA0197NUP120NUP160FUNCTION Functions as a component of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Involved in poly(A)+ RNA transport.SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Forms part of the NUP160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96 (PubMed:11564755, PubMed:11684705). This complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705).CAUTION It is uncertain whether Met-1 or Met-35 is the initiator.UniProtQ127691EQUAL1436EQUALReactome DB_ID: 3762511UniProt:Q8WUM0 NUP133NUP133NUP133FUNCTION Involved in poly(A)+ RNA transport. Involved in nephrogenesis (PubMed:30179222).SUBUNIT Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and Nup96. This complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus.TISSUE SPECIFICITY Widely expressed in fetal and adult tissues. Expressed in the brain and kidney.SIMILARITY Belongs to the nucleoporin Nup133 family.UniProtQ8WUM01EQUAL1156EQUALReactome DB_ID: 3762461UniProt:Q96EE3-1 SEH1LSEH1LSEH1LSEC13LSEH1FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore.FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. The SEH1 subunit appears to be only weakly associated with the Nup107-160 subcomplex. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:17360435, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612).SIMILARITY Belongs to the WD repeat SEC13 family.UniProtQ96EE3-11EQUAL360EQUALReactome DB_ID: 3762471UniProt:P52948-5 NUP98NUP98NUP98ADAR2FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC. May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134).FUNCTION (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and may thereby promote the integration of the virus in the host nucleus (in vitro) (PubMed:23523133). Binding affinity to HIV-1 CA-NC complexes bearing the capsid change ASN-74-ASP is reduced (in vitro) (PubMed:23523133).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:15229283, PubMed:18287282). Interacts directly with NUP96 (PubMed:12191480). Part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96; this complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11684705). Interacts with RAE1 (PubMed:10209021, PubMed:20498086). Does not interact with TPR (PubMed:11684705). Interacts with NUP88 (PubMed:30543681). Interacts directly with NUP88 and NUP214, subunits of the cytoplasmic filaments of the NPC (By similarity). Interacts (via N-terminus) with DHX9 (via DRBM, OB-fold and RGG domains); this interaction occurs in a RNA-dependent manner and stimulates DHX9-mediated ATPase activity (PubMed:28221134).SUBUNIT (Microbial infection) Interacts with vesicular stomatitis virus protein M (PubMed:11106761).DOMAIN Contains G-L-F-G repeats. The FG repeat domains in Nup98 have a direct role in the transport.PTM Isoform 1 to isoform 4 are autoproteolytically cleaved to yield Nup98 and Nup96 or Nup98 only, respectively (PubMed:10087256, PubMed:20407419, PubMed:12191480, PubMed:18287282). Cleaved Nup98 is necessary for the targeting of Nup98 to the nuclear pore and the interaction with Nup96 (PubMed:20407419, PubMed:12191480).PTM Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.DISEASE Chromosomal aberrations involving NUP98 have been found in acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9 (PubMed:8563753). Translocation t(11;17)(p15;p13) with PHF23 (PubMed:17287853).DISEASE A chromosomal aberration involving NUP98 has been found in M0 type acute myeloid leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE Chromosomal aberrations involving NUP98 have been found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NSD1. Translocation t(8;11)(p11.2;p15) with WHSC1L1.DISEASE Chromosomal aberrations involving NUP98 have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE A chromosomal aberration involving NUP98 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with TOP1.DISEASE A chromosomal aberration involving NUP98 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with LNP1.DISEASE A chromosomal aberration involving NUP98 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with PSIP1/LEDGF. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.DISEASE A chromosomal aberration involving NUP98 has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with CCDC28A. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98-CCDC28A in mouse promotes the proliferative capacity and self-renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage.SIMILARITY Belongs to the nucleoporin GLFG family.UniProtP52948-51EQUAL880EQUALReactome DB_ID: 3762371UniProt:Q8NFH4 NUP37NUP37NUP37FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13.UniProtQ8NFH41EQUAL326EQUALReactome Database ID Release 75377883Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377883ReactomeR-HSA-3778832Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377883.2Reactome DB_ID: 1577388UniProt:Q9NRG9 AAASAAASADRACALAGL003AAASFUNCTION Plays a role in the normal development of the peripheral and central nervous system (PubMed:11062474, PubMed:11159947, PubMed:16022285). Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment (PubMed:26246606).SUBUNIT Interacts with NDC1, the interaction is required for nuclear pore localization (PubMed:19782045). Interacts with the inactive form aurora kinase AURKA (PubMed:26246606). Interacts with PGRMC2 (PubMed:27754849).TISSUE SPECIFICITY Widely expressed (PubMed:11159947, PubMed:16022285). Particularly abundant in cerebellum, corpus callosum, adrenal gland, pituitary gland, gastrointestinal structures and fetal lung (PubMed:11159947).UniProtQ9NRG91EQUAL546EQUALReactome DB_ID: 15775332UniProt:Q99567 NUP88NUP88NUP88FUNCTION Component of nuclear pore complex.SUBUNIT Interacts with NUP214/CAN (PubMed:9049309, PubMed:30543681). Interacts with NUP62 and NUP98 (PubMed:30543681).TISSUE SPECIFICITY Ubiquitous.UniProtQ995671EQUAL741EQUALReactome DB_ID: 15769216UniProt:P12270 TPRTPRTPRFUNCTION Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with NUP153, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Negatively regulates both the association of CTE-containing mRNA with large polyribosomes and translation initiation. Does not play any role in Rev response element (RRE)-mediated export of unspliced mRNAs. Implicated in nuclear export of mRNAs transcribed from heat shock gene promoters; associates both with chromatin in the HSP70 promoter and with mRNAs transcribed from this promoter under stress-induced conditions. Modulates the nucleocytoplasmic transport of activated MAPK1/ERK2 and huntingtin/HTT and may serve as a docking site for the XPO1/CRM1-mediated nuclear export complex. According to some authors, plays a limited role in the regulation of nuclear protein export (PubMed:22253824 and PubMed:11952838). Plays also a role as a structural and functional element of the perinuclear chromatin distribution; involved in the formation and/or maintenance of NPC-associated perinuclear heterochromatin exclusion zones (HEZs). Finally, acts as a spatial regulator of the spindle-assembly checkpoint (SAC) response ensuring a timely and effective recruitment of spindle checkpoint proteins like MAD1L1 and MAD2L1 to unattached kinetochore during the metaphase-anaphase transition before chromosome congression. Its N-terminus is involved in activation of oncogenic kinases.SUBUNIT Interacts with IFI204 (via C-terminal region). Interacts with IFI203 (By similarity). Homodimer. Part of the nuclear pore complex (NPC). Associates with the XPO1/CRM1-mediated nuclear export complex, the Importin alpha/Importin beta receptor and the dynein 1 complex. Interacts (via C-terminal domain) with the KPNB1; the interaction occurs in a RanGTP-dependent manner. Interacts (via C-terminal regionand phosphorylated form) with MAPK1/ERK2 (via phosphorylated form); the interaction requires dimerization of MAPK1/ERK2 and increases following EGF stimulation. Interacts with MAPK3/ERK1; the interaction increases following EGF stimulation. Interacts (via coiled coil region) with NUP153; the interaction is direct. Interacts with HSF1; the interaction increases in a stress-responsive manner and stimulates export of stress-induced HSP70 mRNA. Interacts with huntingtin/HTT; the interaction is inhibited by aggregated huntingtin/HTT forms with expanded polyglutamine stretch. Interacts with MAD1L1 (via N-terminal region), MAD2L1, and TTK; the interactions occurs in a microtubule-independent manner. Interacts (via middle region) with DYNLL1. Interacts with DCTN1, dynein, NUP153 and tubulin. Interacts with MTA1.TISSUE SPECIFICITY Expressed in esophagus, ovary, liver, skin, smooth muscles, cerebrum and fetal cerebellum (at protein level). Highest in testis, lung, thymus, spleen and brain, lower levels in heart, liver and kidney.DOMAIN The N-terminal domain mediates intranuclear attachment to the nuclear pore complex. The C-terminal domain mediates its nuclear import.PTM Phosphorylated. Phosphorylation occurs on serine and threonine residues (comprised in the C-terminal region) by MAPK1/ERK2 and stabilizes the interaction between these two proteins.PTM Proteolytically degraded after poliovirus (PV) infection; degradation is restricted to its unfolded C-terminal tail domain whereas its coiled-coil domain containing NCP- and NUP153-binding domains withstand degradation.DISEASE A chromosomal aberration involving TPR has been found in papillary thyroid carcinomas (PTCs). Intrachromosomal rearrangement that links the 5'-end of the TPR gene to the protein kinase domain of NTRK1 forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the carboxy terminus of the NTRK1 protein.DISEASE Involved in tumorigenic rearrangements with the MET.SIMILARITY Belongs to the TPR family.UniProtP122702EQUAL2363EQUALConverted from EntitySet in ReactomeReactome DB_ID: 680516916POM121 [nuclear envelope]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPOM121 [nuclear envelope]POM121C [nuclear envelope]UniProtQ96HA1UniProtA8CG34Converted from EntitySet in ReactomeReactome DB_ID: 29908798NUP98 [nuclear envelope]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNUP98-4 [nuclear envelope]UniProtP52948-4Reactome DB_ID: 15775016UniProt:Q96EE3-2 SEH1LSEH1LSEH1LSEC13LSEH1FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore.FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. The SEH1 subunit appears to be only weakly associated with the Nup107-160 subcomplex. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:17360435, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612).SIMILARITY Belongs to the WD repeat SEC13 family.UniProtQ96EE3-21EQUAL360EQUALReactome DB_ID: 1576918UniProt:P35658 NUP214NUP214NUP214CANKIAA0023CAINFUNCTION Part of the nuclear pore complex (PubMed:9049309). Has a critical role in nucleocytoplasmic transport (PubMed:31178128). May serve as a docking site in the receptor-mediated import of substrates across the nuclear pore complex (PubMed:31178128, PubMed:8108440).FUNCTION (Microbial infection) Required for capsid disassembly of the human adenovirus 5 (HadV-5) leading to release of the viral genome to the nucleus (in vitro).SUBUNIT Homodimer. Part of the nuclear pore complex (NPC) (PubMed:9049309). Interacts with NUP88 (PubMed:9049309, PubMed:30543681). Interacts with ZFP36; this interaction increases upon lipopolysaccharide (LPS) stimulation (PubMed:14766228). Interacts with DDX19 (PubMed:19219046, PubMed:19208808). Interacts with XPO1 (PubMed:9049309). Interacts with XPO5 (PubMed:11777942).SUBUNIT (Microbial infection) Interacts with human herpes virus 1 (HHV-1) protein UL25; this interaction might be essential to the capsid docking onto the host nuclear pore.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 (HAdV-5) protein L3 (hexon); this interaction might be essential for the release of the virus genome to the nucleus.TISSUE SPECIFICITY Expressed in thymus, spleen, bone marrow, kidney, brain and testis, but hardly in all other tissues or in whole embryos during development.DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.DOMAIN The beta-propeller contains long interblade connector loops, and mediates interaction with DDX19B.PTM Probably glycosylated as it reacts with wheat germ agglutinin (WGA).DISEASE A chromosomal aberration involving NUP214 is found in a subset of acute myeloid leukemia (AML); also known as acute non-lymphocytic leukemia. Translocation t(6;9)(p23;q34) with DEK. It results in the formation of a DEK-CAN fusion gene.DISEASE A chromosomal aberration involving NUP214 is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with SET.DISEASE Chromosomal aberrations involving NUP214 are found in acute lymphoblastic leukemia (PubMed:20851865, PubMed:15361874). Translocation t(9;9)(q34;q34) with ABL1 (PubMed:15361874). Translocation t(5;9)(q35;q34) with SQSTM1 (PubMed:20851865).UniProtP356581EQUAL2090EQUALReactome DB_ID: 15769716UniProt:O15504 NUP42NUP42NUP42CG1NUPL2FUNCTION Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm.FUNCTION (Microbial infection) In case of infection by HIV-1, it may participate in the docking of viral Vpr at the nuclear envelope.SUBUNIT Probable component of the nuclear pore complex (NPC). Interacts with nuclear export protein NXF1 (PubMed:10228171). Interacts with GLE1. Able to form a heterotrimer with NUP155 and GLE1 in vitro (PubMed:16000379). Interacts with XPO1 (PubMed:10358091).SUBUNIT (Microbial infection) Interacts with the HIV-1 virus proteins Rev and Vpr. The interaction with HIV-1 Rev, a protein that mediates nuclear export of unspliced viral RNAs, suggests that its function may be bypassed by the HIV-1 virus.TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC.PTM O-glycosylated.UniProtO155041EQUAL423EQUALReactome DB_ID: 15774032UniProt:Q9UKX7 NUP50NUP50NPAP60LNUP50PRO1146FUNCTION Component of the nuclear pore complex that has a direct role in nuclear protein import (PubMed:20016008). Actively displaces NLSs from importin-alpha, and facilitates disassembly of the importin-alpha:beta-cargo complex and importin recycling (PubMed:20016008). Interacts with regulatory proteins of cell cycle progression including CDKN1B (By similarity). This interaction is required for correct intracellular transport and degradation of CDKN1B (By similarity).SUBUNIT Interacts with Importin alpha-2, Importin beta, Importin beta-2, NUP153, Ran binding protein 7, CDKN1B and itself (By similarity). Does not interact with TPR.TISSUE SPECIFICITY Ubiquitous. Highest levels in testis, peripheral blood leukocytes and fetal liver.DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.UniProtQ9UKX71EQUAL468EQUALReactome DB_ID: 15771232Nup62 Complex [nuclear envelope]Nup62 ComplexReactome DB_ID: 1577241UniProt:Q7Z3B4 NUP54NUP54NUP54FUNCTION Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.SUBUNIT Component of the p62 complex, a complex composed of NUP62, NUP54, and the isoform p58 and isoform p45 of NUP58. Interacts with NUTF2.DOMAIN Contains FG repeats.PTM O-glycosylated.SIMILARITY Belongs to the NUP54 family.UniProtQ7Z3B41EQUAL507EQUALReactome DB_ID: 1577131UniProt:P37198 NUP62NUP62NUP62FUNCTION Essential component of the nuclear pore complex (PubMed:1915414). The N-terminal is probably involved in nucleocytoplasmic transport (PubMed:1915414). The C-terminal is involved in protein-protein interaction probably via coiled-coil formation, promotes its association with centrosomes and may function in anchorage of p62 to the pore complex (PubMed:1915414, PubMed:24107630). Plays a role in mitotic cell cycle progression by regulating centrosome segregation, centriole maturation and spindle orientation (PubMed:24107630). It might be involved in protein recruitment to the centrosome after nuclear breakdown (PubMed:24107630).SUBUNIT Component of the p62 complex, a complex at least composed of NUP62, NUP54, and NUP58 (By similarity). Interacts with NUP88 (PubMed:30543681). Interacts with NUTF2 (By similarity). Interacts with HIKESHI (PubMed:22541429). Interacts with OSBPL8 (PubMed:21698267). Interacts with CAPG (PubMed:18266911). Interacts with SAS6 and TUBG1 at the centrosome (PubMed:24107630). Interacts with MCM3AP isoform GANP (PubMed:23652018).SUBUNIT (Microbial infection) Interacts with Epstein-barr virus BGLF4; this interaction allows BGLF4 nuclear entry.DOMAIN Contains FG repeats.PTM O-glycosylated. Contains about 10 N-acetylglucosamine side chain sites predicted for the entire protein, among which only one in the C-terminal.PTM The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC.SIMILARITY Belongs to the nucleoporin NSP1/NUP62 family.UniProtP371981EQUAL522EQUALConverted from EntitySet in ReactomeReactome DB_ID: 96342241NUP58 [nuclear envelope]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNUP58-1 [nuclear envelope]UniProtQ9BVL2-1Reactome Database ID Release 75157712Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157712ReactomeR-HSA-1577122Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157712.2Reactome DB_ID: 680518332UniProt:Q9BTX1 NDC1NDC1NDC1TMEM48FUNCTION Component of the nuclear pore complex (NPC), which plays a key role in de novo assembly and insertion of NPC in the nuclear envelope. Required for NPC and nuclear envelope assembly, possibly by forming a link between the nuclear envelope membrane and soluble nucleoporins, thereby anchoring the NPC in the membrane.SUBUNIT Interacts with the NUP35/NUP53 (By similarity). Interacts with AAAS, anchoring it to the nuclear envelope.MISCELLANEOUS Depletion of NDC1 from HeLa cells interferes with the assembly of phenylalanine-glycine (FG) repeat Nups into nuclear pore complexes.SIMILARITY Belongs to the NDC1 family.UniProtQ9BTX11EQUAL674EQUALReactome DB_ID: 15771848UniProt:P78406 RAE1RAE1MRNP41RAE1FUNCTION Plays a role in mitotic bipolar spindle formation (PubMed:17172455). Binds mRNA. May function in nucleocytoplasmic transport and in directly or indirectly attaching cytoplasmic mRNPs to the cytoskeleton.SUBUNIT Interacts with NUMA1 (via N-terminal end of the coiled-coil domain); this interaction promotes spindle formation in mitosis (PubMed:17172455). Interacts with NUP98 (PubMed:20498086). Interacts with MYCBP2 (PubMed:22357847).SIMILARITY Belongs to the WD repeat rae1 family.UniProtP784061EQUAL368EQUALReactome DB_ID: 15772216UniProt:Q8TEM1 NUP210NUP210NUP210KIAA0906PSEC0245FUNCTION Nucleoporin essential for nuclear pore assembly and fusion, nuclear pore spacing, as well as structural integrity.SUBUNIT Forms dimers and possibly higher-order oligomers.TISSUE SPECIFICITY Ubiquitous expression, with highest levels in lung, liver, pancreas, testis, and ovary, intermediate levels in brain, kidney, and spleen, and lowest levels in heart and skeletal muscle.PTM N-glycosylated, but not all potential glycosylation sites may be used. Contains high-mannose type oligosaccharides (By similarity).PTM Phosphorylated at Ser-1881 in mitosis specifically; not phosphorylated in interphase.MISCELLANEOUS Recognized by antinuclear autoantibodies in primary biliary cirrhosis.MISCELLANEOUS Knockdown of NUP210 causes nuclear membranes to accumulate aberrant structures termed twinned and fusion-arrested membranes and nuclear pore complex to cluster. Induces cell death and chromatin disruptions.SIMILARITY Belongs to the NUP210 family.UniProtQ8TEM127EQUAL1887EQUALReactome DB_ID: 1576958UniProt:P49790 NUP153NUP153NUP153FUNCTION Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with TPR, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Mediates TPR anchoring to the nuclear membrane at NPC. The repeat-containing domain may be involved in anchoring other components of the NPC to the pore membrane. Possible DNA-binding subunit of the nuclear pore complex (NPC).FUNCTION (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and thereby promotes the integration of the virus in the nucleus of non-dividing cells (in vitro).FUNCTION (Microbial infection) Binds HIV-2 protein vpx and thereby promotes the nuclear translocation of the lentiviral genome (in vitro).SUBUNIT Interacts with RAN; the interaction occurs in a GTP- and GDP-independent manner (By similarity). Part of the nuclear pore complex (NPC). Interacts with TPR (via coiled coil region); the interaction is direct and provides a link between the core structure and the TPR-containing nuclear basket of the nuclear pore complex (NPC). Interacts with HIKESHI, SENP2 and XPO5. Interacts with MCM3AP isoform GANP; this interaction is required for GANP localization at the nuclear pore complex (PubMed:20005110, PubMed:23652018).SUBUNIT (Microbial infection) Interacts (via C-terminus) with HIV-1 capsid protein p24 (CA) (via N-terminus).SUBUNIT (Microbial infection) Interacts with HIV-1 integrase; this interaction might play a role in nuclear import of HIV pre-integration complex.SUBUNIT (Microbial infection) Interacts with hepatitis B virus capsid protein; this interaction probably plays a role in nuclear import of HBV genome.SUBUNIT (Microbial infection) Interacts with Epstein-barr virus BGLF4; this interaction allows BGLF4 nuclear entry.SUBUNIT (Microbial infection) Interacts with HIV-2 virus protein vpx; this interaction might promote vpx nuclear entry.DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.DOMAIN (Microbial infection) FG repeats mediates interaction with HIV-1 capsid protein p24 (CA).PTM Phosphorylated in interphase, hyperphosphorylated during mitosis. May play a role in the reversible disassembly of the nuclear pore complex during mitosis (By similarity).PTM Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.PTM O-glycosylated during cytokinesis at sites identical or close to phosphorylation sites, this interferes with the phosphorylation status.SIMILARITY Belongs to the NUP153 family.UniProtP497902EQUAL1475EQUALReactome Database ID Release 75157689Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157689ReactomeR-HSA-1576894Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157689.4GO0017056GO molecular functionReactome Database ID Release 75450099Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450099Reactome Database ID Release 751176059Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1176059ReactomeR-HSA-11760596Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1176059.615702989Pubmed2005An unconventional NLS is critical for the nuclear import of the influenza A virus nucleoprotein and ribonucleoproteinCros, JFGarcia-Sastre, APalese, PTraffic 6:205-137559393Pubmed1995Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein importO'Neill, REJaskunas, RBlobel, GPalese, PMoroianu, JJ Biol Chem 270:22701-417376915Pubmed2007Nuclear and nucleolar targeting of influenza A virus NS1 protein: striking differences between different virus subtypesMelén, KKinnunen, LFagerlund, RIkonen, NTwu, KYKrug, RMJulkunen, IJ Virol 81:5995-6006GO0075733GO biological processINHIBITIONReactome Database ID Release 751176075Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1176075ReactomeR-HSA-11760751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1176075.1Reactome DB_ID: 1169392Monoubiquitination of N-myristoyl GAG (P12493) proteinMonoubiquitination of N-myristoyl GAG (P12493) proteinCytosolic N-myristoyl Gag polyprotein is conjugated with a single molecule of ubiquitin. Conjugation is typically to one of two lysine residues in the p6 domain of Gag but can be to lysine residues in the MA, CA, NC, and SP2 domains of the protein. The specific host cell E2 and E3 proteins that mediate Gag ubiquitination have not been identified. The same studies that first identified the p6 ubiquitination sites in Gag also called the biological significance of Gag ubiquitination into question by demonstrating that Gag proteins in which the p6 ubiquitination sites had been removed by mutagenesis could still assemble efficiently into infectious viral particles (Ott et al. 1998, 2000). More recent work, however, has identified additional ubiquitination sites throughout the C-terminal region of the Gag polyprotein, and when all of these sites are removed by mutagenesis, both viral assembly involving the mutant Gag polyprotein and infectivity of the resulting viral particles are sharply reduced (Gottwein et al. 2006). Note: Reactions directly involving interactions of human host proteins with foreign ones are highlighted in red.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Converted from EntitySet in ReactomeReactome DB_ID: 1135951Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBC(229-304) [cytosol]UBC(153-228) [cytosol]UBC(609-684) [cytosol]UBB(77-152) [cytosol]UBC(1-76) [cytosol]UBC(457-532) [cytosol]UBC(77-152) [cytosol]UBC(305-380) [cytosol]UBA52(1-76) [cytosol]RPS27A(1-76) [cytosol]UBB(153-228) [cytosol]UBC(533-608) [cytosol]UBC(381-456) [cytosol]UBB(1-76) [cytosol]UniProtP0CG48UniProtP0CG47UniProtP62987UniProtP62979Reactome DB_ID: 1844031UniProt:P12493 gaggaggagDOMAIN Late-budding domains (L domains) are short sequence motifs essential for viral particle budding. They recruit proteins of the host ESCRT machinery (Endosomal Sorting Complex Required for Transport) or ESCRT-associated proteins. p6-gag contains two L domains: a PTAP/PSAP motif, which interacts with the UEV domain of TSG101 and a LYPX(n)L motif which interacts with PDCD6IP/AIP1.PTM Gag-Pol polyprotein: Specific enzymatic cleavages by the viral protease yield mature proteins.MISCELLANEOUS The infectious clone pNL4-3 is a chimeric provirus that consists of DNA from HIV isolates NY5 (5' half) and BRU (3' half).MISCELLANEOUS HIV-1 lineages are divided in three main groups, M (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast majority of strains found worldwide belong to the group M. Group O seems to be endemic to and largely confined to Cameroon and neighboring countries in West Central Africa, where these viruses represent a small minority of HIV-1 strains. The group N is represented by a limited number of isolates from Cameroonian persons. The group M is further subdivided in 9 clades or subtypes (A to D, F to H, J and K).SIMILARITY Belongs to the primate lentivirus group gag polyprotein family.Human immunodeficiency virus 1NCBI Taxonomy11676UniProtP12493N-myristoylglycine at 11EQUALN-myristoylglycine [MOD:00068]Reactome DB_ID: 1842731monoubiquitinated N-myristoyl GAG (P12493) protein [cytosol]monoubiquitinated N-myristoyl GAG (P12493) proteinConverted from EntitySet in ReactomeReactome DB_ID: 1135951Reactome DB_ID: 1844031N-myristoylglycine at 11EQUALReactome Database ID Release 75184273Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=184273ReactomeR-HSA-1842732Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-184273.2Reactome Database ID Release 751169307Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169307ReactomeR-HSA-11693073Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169307.39525617Pubmed1998Ubiquitin is covalently attached to the p6Gag proteins of human immunodeficiency virus type 1 and simian immunodeficiency virus and to the p12Gag protein of Moloney murine leukemia virusOtt, DECoren, LVCopeland, TDKane, BPJohnson, DGSowder RC, 2ndYoshinaka, YOroszlan, SArthur, LOHenderson, LEJ Virol 72:2962-816775314Pubmed2006Cumulative mutations of ubiquitin acceptor sites in human immunodeficiency virus type 1 gag cause a late budding defectGottwein, EJager, SHabermann, AKrausslich, HGJ Virol 80:6267-7511112487Pubmed2000Ubiquitination of HIV-1 and MuLV GagOtt, DECoren, LVChertova, ENGagliardi, TDSchubert, UVirology 278:111-21INHIBITIONOver expression of ISG15 inhibits the release of HIV -1 virions. ISG15 mainly inhibits the ubiquitination of viral GAG and host Tsg101 proteins and disrupts their interaction, thereby preventing assembly and release of virions.Reactome Database ID Release 751169312Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169312ReactomeR-HSA-11693122Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169312.2Reactome DB_ID: 9365522EQUAL157EQUALRegulation of protein ISGylation by ISG15 deconjugating enzyme USP18Regulation of protein ISGylation by ISG15 deconjugating enzyme USP18Ubiquitin specific protease 18 (USP18/UBP43) is the major ISG15 deconjugating enzyme. It removes ISG15 from ISGylated proteins. ISG15-specific protease activity of this enzyme is crucial for proper cellular balance of ISG15-conjugated proteins. However, it is not required for processing pre-ISG15 to the mature form. Furthermore, USP18 inhibits type I interferon signaling independent of its ISG15 deconjugating enzyme activity. Several viral proteins were also reported with de-ISGylation activity.Authored: Garapati, P V, 2011-01-18Reviewed: Zhang, DE, 2011-02-10Edited: Garapati, P V, 2011-01-18Reactome DB_ID: 11693871Converted from EntitySet in ReactomeReactome DB_ID: 11693791Reactome DB_ID: 1416811polypeptide [cytosol]polypeptidePHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 4127442USP18-like proteins [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUSP18 [cytosol]UniProtQ9UMW8GO0019785GO molecular functionReactome Database ID Release 751678840Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678840Reactome Database ID Release 751678841Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678841ReactomeR-HSA-16788412Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1678841.216710296Pubmed2006UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activityMalakhova, OAKim, KILuo, JKZou, WKumar, KGFuchs, SYShuai, KZhang, DEEMBO J 25:2358-6720181693Pubmed2010Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteasesClementz, MAChen, ZBanach, BSWang, YSun, LRatia, KBaez-Santos, YMWang, JTakayama, JGhosh, AKLi, KMesecar, ADBaker, SCJ Virol 84:4619-2911788588Pubmed2002UBP43 (USP18) specifically removes ISG15 from conjugated proteinsMalakhov, MPMalakhova, OAKim, KIRitchie, KJZhang, DEJ Biol Chem 277:9976-8117692280Pubmed2007Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like proteaseLindner, HALytvyn, VQi, HLachance, PZiomek, EMenard, RArch Biochem Biophys 466:8-14Reactome Database ID Release 751169408Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169408ReactomeR-HSA-11694082Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169408.215970528Pubmed2005ISG15: a ubiquitin-like enigmaDao, CTZhang, DEFront Biosci 10:2701-22OAS antiviral responseOAS antiviral responseThe human oligoadenylate synthetase (OAS) family consists of four proteins whose production is stimulated by interferon, OAS1, OAS2, OAS3, and OASL. The first three members have the 2'-5'-oligoadenylate synthetase activity for which the family is named (Sadler AJ & Williams BR 2008), whereas OASL is devoid of this activity despite sharing significant sequence similarity with the other OAS proteins (Zhu J et al. 2015). OAS1, 2, and 3 are activated by double-stranded RNA to synthesize 5'-triphosphorylated 2'-5'-oligoadenylates (2-5A) from ATP (Kerr IM & Brown RE 1978). The 2-5A serve as chemically unique second messengers that induce regulated RNA decay by activating ribonuclease L (RNase L), thus mediating antiviral innate immunity (Zhou A et al. 1993; Lin RJ et al. 2009; Huang H et al. 2014; Han Y et al. 2014). RNase L has also been implicated in antibacterial innate immunity (Li XL et al. 2008). RNase L cleaves single-stranded RNA (ssRNA) in U-rich sequences, typically after UU or UA dinucleotides leaving a 5'-OH and 2',3'-cyclic phosphate (Floyd-Smith G et al. 1981; Wreschner DH et al.1981; Cooper DA et al. 2014).<p>Some OAS proteins have additional or alternative antiviral functions that are independent of RNase L activity (Perelygin AA et al., 2002; Kristiansen H et al. 2011). The precise mechanisms of RNase L-independent OAS antiviral activities remain to be fully elucidated.Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31OAS1 binds viral dsRNAOAS1 binds viral dsRNAHuman oligoadenylate synthetase 1 (OAS1) recognizes double-stranded RNA (dsRNA) typically produced by viral infections. The X-ray crystal structure of human OAS1 bound to a model 18-bp dsRNA duplex revealed that dsRNA binding allosterically drives a functionally essential structural reorganization within human OAS1 that narrows the adenosine triphosphate (ATP)-binding cleft and repositions a catalytic residue to complete its active site (Donovan J et al. 2013). Once stimulated by dsRNA, OAS1 uses ATP to synthesize a series of 5'-triphosphorylated 2'-5'-linked oligoadenylates containing 2 to greater than 5 adenylyl residues. The 5'-triphosphorylated 2'-5’-linked triadenylate (i.e., ppp5’A2’p5’A2’p5’A) is typically the most abundant active species (Kerr IM & Brown RE 1978).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 9474861UniProt:P00973 OAS1OAS1OAS1OIASFUNCTION Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation. Synthesizes higher oligomers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication. Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L. The secreted form displays antiviral effect against vesicular stomatitis virus (VSV), herpes simplex virus type 2 (HSV-2), and encephalomyocarditis virus (EMCV) and stimulates the alternative antiviral pathway independent of RNase L.ACTIVITY REGULATION Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection. The dsRNA activator must be at least 15 nucleotides long, and no modification of the 2'-hydroxyl group is tolerated. ssRNA or dsDNA do not act as activators.SUBUNIT Monomer (PubMed:9407111). Homotetramer (PubMed:9407111, PubMed:23319625).INDUCTION By type I interferon (IFN) and viruses.SIMILARITY Belongs to the 2-5A synthase family.CAUTION PubMed:1651324 sequence was originally thought to originate from mouse.UniProtP009731EQUAL400EQUALConverted from EntitySet in ReactomeReactome DB_ID: 90377131OAS1 ligand [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 89836901OAS1:OAS1 ligand [cytosol]OAS1:OAS1 ligandReactome DB_ID: 94748611EQUAL400EQUALConverted from EntitySet in ReactomeReactome DB_ID: 90377131Reactome Database ID Release 758983690Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8983690ReactomeR-HSA-89836901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983690.1Reactome Database ID Release 758983671Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8983671ReactomeR-HSA-89836711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983671.1272640Pubmed1978pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cellsKerr, I MBrown, R EProc. Natl. Acad. Sci. U.S.A. 75:256-6023319625Pubmed2013Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1Donovan, JesseDufner, MatthewKorennykh, AlexeiProc. Natl. Acad. Sci. U.S.A. 110:1652-7OAS1 oligomerizesOAS1 oligomerizesThe tetramerization of 2'-5'-oligoadenylate synthetase OAS1 is required for enzymatic activity (Ghosh A et al. 1997).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 89836904Reactome DB_ID: 89836291OAS1 tetramer:OAS1 ligand [cytosol]OAS1 tetramer:OAS1 ligandReactome DB_ID: 89836904Reactome Database ID Release 758983629Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8983629ReactomeR-HSA-89836291Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983629.1Reactome Database ID Release 758983688Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8983688ReactomeR-HSA-89836881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983688.19407111Pubmed1997Enzymatic activity of 2'-5'-oligoadenylate synthetase is impaired by specific mutations that affect oligomerization of the proteinGhosh, ASarkar, S NGuo, WBandyopadhyay, SSen, G CJ. Biol. Chem. 272:33220-62.7.7.84OAS1 produces oligoadenylatesOAS1 produces oligoadenylatesOligoadenylate synthetase 1 (OAS1) produces the second messenger 5’-triphosphorylated 2'-5'-oligoadenylate (2-5A), which limits viral propagation through the activation of the enzyme RNase L (reviewed by Silverman RH 2007; Hornung V et al. 2014). OAS1 produces 2-5A from ATP by transferring an AMP unit from the AMP donor substrate (ATP) to the 2′-hydroxyl group of an AMP acceptor substrate, ATP or a preformed 2-5A oligomer (Lohofener J et al. 2015). This produces a 2-5A dimer (ppp5'A(2'-5')A) or an elongated 2-5A oligomer (ppp5'A((2'-5')A)n), as well as one molecule of pyrophosphate (PPi) for each AMP residue added (Lohofener J et al. 2015). Structural studies showed that RNA-induced conformational rearrangement in OAS1 positions the active site residues D75, D77, and D148 compactly for coordination of two Mg2+ ions and for binding of ATP (Donovan J et al. 2013). The assembly of this critical active-site structure of OAS1 provides the gate that couples binding of dsRNA to the production and downstream functions of 2-5A, enabling OAS1 to function as a sensor of double-stranded RNA (dsRNA) (Donovan J et al. 2013).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 1135923Reactome DB_ID: 898369612'-5' oligoadenylate [cytosol]2'-5' oligoadenylateReactome DB_ID: 1112942PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8983629GO0001730GO molecular functionReactome Database ID Release 758983641Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8983641Reactome Database ID Release 758983680Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8983680ReactomeR-HSA-89836801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983680.125892109Pubmed2015The Activation Mechanism of 2'-5'-Oligoadenylate Synthetase Gives New Insights Into OAS/cGAS Triggers of Innate ImmunityLohöfener, JanSteinke, NicolaKay-Fedorov, PenelopeBaruch, PetraNikulin, AlexeyTishchenko, SvetlanaManstein, Dietmar JFedorov, RomanStructure 23:851-6225033909Pubmed2014OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acidsHornung, VeitHartmann, RuneAblasser, AHopfner, KPNat. Rev. Immunol. 14:521-817804500Pubmed2007Viral encounters with 2',5'-oligoadenylate synthetase and RNase L during the interferon antiviral responseSilverman, Robert HJ. Virol. 81:12720-9OAS2 binds viral dsRNAOAS2 binds viral dsRNAThe human oligoadenylate synthetase 2 (OAS2) is activated by double-stranded RNA (dsRNA) (Hovanessian AG et al. 1988; Behera AK et al. 2002; Kristiansen H et al. 2011).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 10156891UniProt:P29728 OAS2OAS2OAS2FUNCTION Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response (PubMed:10464285, PubMed:9880569). Activated by detection of double stranded RNA (dsRNA): polymerizes higher oligomers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNASEL) leading to its dimerization and subsequent activation (PubMed:10464285, PubMed:9880569, PubMed:11682059). Activation of RNASEL leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication (PubMed:10464285, PubMed:9880569). Can mediate the antiviral effect via the classical RNASEL-dependent pathway or an alternative antiviral pathway independent of RNASEL (PubMed:21142819). In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation (PubMed:21142819). May act as a negative regulator of lactation, stopping lactation in virally infected mammary gland lobules, thereby preventing transmission of viruses to neonates (By similarity). Non-infected lobules would not be affected, allowing efficient pup feeding during infection (By similarity).ACTIVITY REGULATION Produced as a latent enzyme which is activated by double stranded RNA (dsRNA) generated during the course of viral infection(PubMed:9880569). The dsRNA activator must be at least 15 nucleotides long, and no modification of the 2'-hydroxyl group is tolerated (PubMed:9880569). ssRNA or dsDNA do not act as activators (PubMed:9880569). Strongly inhibited by copper, iron and zinc ions (PubMed:11682059). Partially inhibited by cobalt and nickel ions (PubMed:11682059).SUBUNIT Homodimer.INDUCTION By type I interferon (IFN) and viruses.PTM Myristoylation is not essential for its activity.PTM Glycosylated. Glycosylation is essential for its activity.SIMILARITY Belongs to the 2-5A synthase family.UniProtP297282EQUAL719EQUALReactome DB_ID: 89850531RSV dsRNA intermediate form [cytosol]RSV dsRNA intermediate formReactome DB_ID: 89850501OAS2:OAS2 ligand [cytosol]OAS2:OAS2 ligandReactome DB_ID: 101568912EQUAL719EQUALReactome DB_ID: 89850531Reactome Database ID Release 758985050Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985050ReactomeR-HSA-89850501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985050.1Reactome Database ID Release 758985138Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985138ReactomeR-HSA-89851381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985138.19880569Pubmed1999Enzymatic characteristics of recombinant medium isozyme of 2'-5' oligoadenylate synthetaseSarkar, S NBandyopadhyay, SGhosh, ASen, G CJ. Biol. Chem. 274:1848-5511980899Pubmed20022'-5' Oligoadenylate synthetase plays a critical role in interferon-gamma inhibition of respiratory syncytial virus infection of human epithelial cellsBehera, Aruna KKumar, MukeshLockey, Richard FMohapatra, Shyam SJ. Biol. Chem. 277:25601-83350819Pubmed1988Characterization of 69- and 100-kDa forms of 2-5A-synthetase from interferon-treated human cellsHovanessian, A GSvab, JMarié, IRobert, NChamaret, SLaurent, A GJ. Biol. Chem. 263:4945-911986302Pubmed2002Identification of the substrate-binding sites of 2'-5'-oligoadenylate synthetaseSarkar, Saumendra NMiyagi, MasaruCrabb, John WSen, Ganes CJ. Biol. Chem. 277:24321-3021142819Pubmed2011The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activitiesKristiansen, HelleGad, Hans HenrikEskildsen-Larsen, SigneDespres, PhilippeHartmann, RuneJ. Interferon Cytokine Res. 31:41-7OAS2 dimerizesOAS2 dimerizesGel filtration experiments using extracts from IFN-treated human HeLa and Daudi cells showed that 2',5'-oligoadenylate (2-5A) synthetase (OAS2, p69) exists as a dimer of 160 kDa (Marie I et al. 1990). Biochemical and mutational studies demonstrated that dimerization of OAS2 protein is required for its enzyme activity (Sarkar SN et al. 1999). Further, photo affinity cross-linking and peptide mapping to study the substrate binding sites in OAS2 have suggested that OAS2 is active only as a dimer because it catalyzes the joining of the acceptor substrate bound to one subunit to the donor substrate bound to the other subunit (Sarkar SN et al. 2002). Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 89850502Reactome DB_ID: 89850311OAS2:OAS2 ligand dimer [cytosol]OAS2:OAS2 ligand dimerReactome DB_ID: 89850502Reactome Database ID Release 758985031Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985031ReactomeR-HSA-89850311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985031.1Reactome Database ID Release 758985097Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985097ReactomeR-HSA-89850971Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985097.110464285Pubmed1999The nature of the catalytic domain of 2'-5'-oligoadenylate synthetasesSarkar, S NGhosh, AWang, H WSung, S SSen, G CJ. Biol. Chem. 274:25535-422211721Pubmed1990Differential expression and distinct structure of 69- and 100-kDa forms of 2-5A synthetase in human cells treated with interferonMarié, ISvab, JRobert, NGalabru, JHovanessian, AGJ Biol Chem 265:18601-72.7.7.84OAS2 produces oligoadenylatesOAS2 produces oligoadenylates2'-5'-oligoadenylate synthetase 2 (OAS2) polymerizes ATP into 5'-triphosphorylated, 2'-5'-linked oligoadenylate (2-5A) (Hovanessian AG et al. 1988; Sarkar SN et al. 1999, 2002). 2-5A molecules are recognized by ribonuclease L (RNase L) (Han Y et al. 2014; Huang H et al. 2014). Activated RNase L cleaves viral and cellular RNA resulting in the inhibition of viral replication (Silverman RH 2007).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 1135923Reactome DB_ID: 89836961Reactome DB_ID: 1112942PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8985031Reactome Database ID Release 758985045Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985045Reactome Database ID Release 758985104Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985104ReactomeR-HSA-89851041Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985104.124578532Pubmed2014Structure of human RNase L reveals the basis for regulated RNA decay in the IFN responseHan, YuchenDonovan, JesseRath, SnehaWhitney, GenaChitrakar, AlishaKorennykh, AlexeiScience 343:1244-824462203Pubmed2014Dimeric structure of pseudokinase RNase L bound to 2-5A reveals a basis for interferon-induced antiviral activityHuang, HaoZeqiraj, EltonDong, BeihuaJha, Babal KantDuffy, Nicole MOrlicky, StephenThevakumaran, NeroshanTalukdar, ManishaPillon, Monica CCeccarelli, Derek FWan, Leo C KJuang, Yu-ChiMao, Daniel Y LGaughan, ChristinaBrinton, Margo APerelygin, Andrey AKourinov, IgorGuarné, AlbaSilverman, Robert HSicheri, FrankMol. Cell 53:221-34OAS3 binds viral dsRNAOAS3 binds viral dsRNAViral dsRNA-activated oligoadenylate synthetase 3 (OAS3) exhibits a strong preference for long dsRNA. A study that included the crystal structure of the N-terminal enzymatically inactive 2'-5' oligoadenylate synthetase domain of human OAS3 (hOAS3.DI) in complex with 19-bp dsRNA indicated that this domain I (DI) subunit has high affinity for the binding of long (>50 bp) dsRNA, which then is presented to the enzymatically active C-terminal domain III (DIII) of OAS3 that produces 5’-triphosphorylated 2'-5' olgoadenylates from ATP (Donovan J et al. 2015). OAS3 was reported to be the major antiviral human OAS isoform (Li Y et al. 2016).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 10156721UniProt:Q9Y6K5 OAS3OAS3OAS3P/OKcl.4FUNCTION Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation. Synthesizes preferentially dimers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication. Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L. Displays antiviral activity against Chikungunya virus (CHIKV), Dengue virus, Sindbis virus (SINV) and Semliki forest virus (SFV).ACTIVITY REGULATION Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection (Probable). Strongly activated by long dsRNAs at least 50 nucleotides in length (PubMed:25775560). ssRNA does not activate the enzyme (PubMed:25775560).SUBUNIT Monomer.TISSUE SPECIFICITY Present at high level in placenta trophoblast.INDUCTION By type I interferon (IFN) and viruses.DOMAIN OAS domain 3 is catalytically active. OAS domain 1 has no catalytic activity but is essential for recognition of long dsRNAs.SIMILARITY Belongs to the 2-5A synthase family.UniProtQ9Y6K51EQUAL1087EQUALConverted from EntitySet in ReactomeReactome DB_ID: 89850761OAS3 ligand [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 89851561OAS3:OAS3 ligand [cytosol]OAS3:OAS3 ligandReactome DB_ID: 101567211EQUAL1087EQUALConverted from EntitySet in ReactomeReactome DB_ID: 89850761Reactome Database ID Release 758985156Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985156ReactomeR-HSA-89851561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985156.1Reactome Database ID Release 758985157Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985157ReactomeR-HSA-89851571Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985157.125775560Pubmed2015Structural mechanism of sensing long dsRNA via a noncatalytic domain in human oligoadenylate synthetase 3Donovan, JesseWhitney, GenaRath, SnehaKorennykh, AlexeiProc. Natl. Acad. Sci. U.S.A. 112:3949-5426858407Pubmed2016Activation of RNase L is dependent on OAS3 expression during infection with diverse human virusesLi, YizeBanerjee, ShuvojitWang, YuyanGoldstein, Stephen ADong, BeihuaGaughan, ChristinaSilverman, Robert HWeiss, Susan RProc. Natl. Acad. Sci. U.S.A. 113:2241-62.7.7.84OAS3 produces oligoadenylatesOAS3 produces oligoadenylates2'-5'-oligoadenylate synthetase 3 (OAS3) is a template-independent nucleotidyl transferase that, once activated by double-stranded RNA in the cytosol, produces second messenger molecules 5'-triphosphorylated 2′,5′-linked oligoadenylates (2-5A). OAS3 was reported to produce preferentially dimeric 2-5A (Rebouillat D et al. 1999). However recent reports showed that OAS3 is able to synthesize 2',5'-oligoadenylates of sufficient length (the triadenylate and longer) to activate RNase L and thus limit viral propagation (Ibsen MS et al. 2014; Li Y et al. 2016).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 1135923Reactome DB_ID: 89836961Reactome DB_ID: 1112942PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8985156Reactome Database ID Release 758985036Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985036Reactome Database ID Release 758985091Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985091ReactomeR-HSA-89850911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985091.125275129Pubmed2014The 2'-5'-oligoadenylate synthetase 3 enzyme potently synthesizes the 2'-5'-oligoadenylates required for RNase L activationIbsen, Mikkel SøesGad, Hans HenrikThavachelvam, KarthigaBoesen, ThomasDesprès, PhilippeHartmann, RuneJ. Virol. 88:14222-319880533Pubmed1999The 100-kDa 2',5'-oligoadenylate synthetase catalyzing preferentially the synthesis of dimeric pppA2'p5'A molecules is composed of three homologous domainsRebouillat, DHovnanian, AMarié, IHovanessian, A GJ. Biol. Chem. 274:1557-65OASL binds DDX58OASL binds DDX58Interferon-dependent antiviral mechanisms trigger activation of 5'-triphosphorylated 2'-5'oligoadenylate synthetase (OAS) proteins which bind double-stranded RNA and catalyze the synthesis of 5'-triphosphorylated 2'-5' oligoadenylates from ATP (Kristiansen et al. 2011). The p59 protein encoded by the OAS-like (OASL) gene is an atypical member of the OAS family in the sense that it lacks the characteristic 2'-5' oligoadenylate synthetase activity (Hartmann et al. 1998; Rebouillat et al. 1998). Furthermore, OASL contains two tandem ubiquitin-like domains (UBL) in the C-terminus, which are absent in other OAS proteins (Hartmann et al. 1998; Rebouillat et al. 1998). OASL is rapidly induced by virus infection via interferon regulatory factor 3 (IRF3) as well as by IFN signaling and has been shown to have antiviral activities, which requires the UBL domain (Melchjorsen et al. 2009; Sarkar and Sen 2004; Marques et al. 2008; Schoggins et al. 2011). OASL is thought to interact with and enhance RIG1 (DDX58) signaling through its C-terminal ubiquitin-like domain (UBL) by mimicking polyubiquitin (Zhu J et al. 2014). Loss of OASL expression reduced DDX58 signaling and enhanced virus replication in human cells. Conversely, OASL expression suppressed replication of a number of viruses in a DDX58-dependent manner and enhanced DDX58-mediated IFN induction (Zhu J et al. 2014).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 10156781UniProt:Q15646 OASLOASLTRIP14OASLFUNCTION Does not have 2'-5'-OAS activity, but can bind double-stranded RNA. Displays antiviral activity against encephalomyocarditis virus (EMCV) and hepatitis C virus (HCV) via an alternative antiviral pathway independent of RNase L.SUBUNIT Specifically interacts with the ligand binding domain of the thyroid receptor (TR). TRIP14 does not require the presence of thyroid hormone for its interaction. Binds MBD1.TISSUE SPECIFICITY Expressed in most tissues, with the highest levels in primary blood Leukocytes and other hematopoietic system tissues, colon, stomach and to some extent in testis.INDUCTION By type I interferon (IFN) and viruses.DOMAIN The ubiquitin-like domains are essential for its antiviral activity.SIMILARITY Belongs to the 2-5A synthase family.CAUTION This is the ortholog of mouse OASL1.UniProtQ156461EQUAL514EQUALReactome DB_ID: 1689171UniProt:O95786 DDX58DDX58DDX58FUNCTION Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and proinflammatory cytokines. Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments. The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531). Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (&lt;1 kb in length). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential. Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity. A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity. Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV). It also detects rotaviruses and reoviruses. Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.SUBUNIT Monomer; maintained as a monomer in an autoinhibited state. Upon binding of viral RNAs and conformational shift, homooligomerizes and forms filaments on these molecules (PubMed:26471729). Interacts (via tandem CARD domain) with MAVS/IPS1 promoting its filamentation. Interacts with DHX58/LGP2, IKBKE, TBK1 and STING1. Interacts (via CARD domain) with TRIM25 (via SPRY domain). Interacts (double-stranded RNA-bound oligomeric form) with RNF135 (homodimer); involved in RNA length-dependent activation of the RIG-I signaling pathway (PubMed:19017631, PubMed:19484123, PubMed:23950712, PubMed:28469175, PubMed:31006531). Interacts with CYLD. Interacts with NLRC5; blocks the interaction of MAVS/IPS1 to DDX58. Interacts with SRC. Interacts with DDX60. Interacts with isoform 2 of ZC3HAV1 (via zinc-fingers) in an RNA-dependent manner. Interacts (via tandem CARD domain) with SEC14L1; the interaction is direct and impairs the interaction of DDX58 with MAVS/IPS1. Interacts with VCP/p97; interaction is direct and allows the recruitment of RNF125 and subsequent ubiquitination and degradation (PubMed:26471729). Interacts with NOP53; may regulate DDX58 through USP15-mediated 'Lys-63'-linked deubiquitination (PubMed:27824081). Interacts with SIGLEC10, CBL and PTPN11; within a negative feedback loop leading to DDX58 degradation (By similarity). Interacts with LRRC25 (PubMed:29288164). Interacts with ZCCHC3; leading to activation of DDX58/RIG-I (PubMed:30193849). Interacts with RNF123 (PubMed:27312109). Interacts with UBE2D3 and UBE2N; E2 ubiquitin ligases involved in RNF135-mediated ubiquitination of DDX58 and activation of the RIG-I signaling pathway (PubMed:28469175). Interacts with IFIT3 (PubMed:21813773). Interacts with DDX3X (PubMed:20127681).SUBUNIT (Microbial infection) Interacts with protein Z of Guanarito virus, Machupo virus, Junin arenavirus and Sabia virus. This interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 and NF-kappa-B activation and resulting in decreased IFN-beta induction (PubMed:20007272).SUBUNIT (Microbial infection) Interacts (via CARD domain) with Human respiratory syncytial virus A non-structural protein 2 (NS2) and this interaction disrupts its interaction with MAVS/IPS1, impeding downstream IRF3 activation (PubMed:19193793).SUBUNIT (Microbial infection) Interacts with Rotavirus A non-structural protein 1 (NSP1) and this interaction induces down-regulation of DDX58/RIG-I (PubMed:22152002).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein US11; this interaction prevents the interaction of MAVS/IPS1 to DDX58 (PubMed:22301138).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL37; this interaction deaminates DDX58 and inhibits its activation.TISSUE SPECIFICITY Present in vascular smooth cells (at protein level).INDUCTION By bacterial lipopolysaccharides (LPS) in endothelial cells. By interferon (IFN).DOMAIN The RLR CTR domain controls homooligomerization and interaction with MAVS/IPS1. In the absence of viral infection, the protein is maintained as a monomer in an autoinhibited state with the CARD domains masked through intramolecular interactions with the RLR CTR domain. Upon binding to viral RNA and ubiquitination by RNF135, a conformational change releases the autoinhibition promoting further homooligomerization, interaction of the CARD domains with the adapter protein MAVS/IPS1 and activation of the downstream RIG-I signaling pathway.DOMAIN The helicase domain is responsible for dsRNA recognition.DOMAIN The 2 CARD domains are responsible for interaction with and signaling through MAVS/IPS1 and for association with the actin cytoskeleton.DOMAIN The second CARD domain is the primary site for 'Lys-63'-linked ubiquitination.PTM (Microbial infection) Deamidated on 'Asn-495' and 'Asn-549' by herpes simplex virus 1 protein UL37. These modifications eliminate DDX58 detection of viral RNA and restriction of viral replication.PTM (Microbial infection) Cleaved by the protease 3C of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production.PTM Phosphorylated in resting cells and dephosphorylated in RNA virus-infected cells. Phosphorylation at Thr-770, Ser-854 and Ser-855 results in inhibition of its activity while dephosphorylation at these sites results in its activation.PTM ISGylated. Conjugated to ubiquitin-like protein ISG15 upon IFN-beta stimulation. ISGylation negatively regulates its function in antiviral signaling response.PTM Sumoylated, probably by MUL1; inhibiting its polyubiquitination.PTM Ubiquitinated. 'Lys-63' ubiquitination by RNF135, which occurs after RNA-binding and homodimerization, releases the autoinhibition of the CARD domains by the RLR CTR domain, an essential step in the activation of the RIG-I signaling pathway (PubMed:23950712, PubMed:28469175, PubMed:31006531). Lys-172 is the critical site of ubiquitination for MAVS/IPS1 binding and to induce anti-viral signal transduction (PubMed:17392790, PubMed:30193849). Lys-154, Lys-164 and Lys-172 are shared sites for RNF135-mediated and TRIM4-mediated ubiquitination (PubMed:19017631, PubMed:19484123, PubMed:24755855). Also undergoes 'Lys-48' ubiquitination at Lys-181 by RNF125 that leads to proteasomal degradation (PubMed:17460044, PubMed:26471729). 'Lys-48' ubiquitination follows viral infection and is enhanced by 'Lys-63'-linked ubiquitination of the CARD domains that promotes interaction with VCP/p97 and subsequent recruitment of RNF125 (PubMed:17460044, PubMed:26471729). Within a negative feedback loop involving SIGLEC10 and PTPN11, 'Lys-48' ubiquitination at Lys-812 by CBL also elicits the proteasomal degradation of DDX58 (By similarity). Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:18636086). Also probably deubiquitinated by USP17L2/USP17 that cleaves 'Lys-48'- and 'Lys-63'-linked ubiquitin chains and positively regulates the receptor (PubMed:20368735).SIMILARITY Belongs to the helicase family. RLR subfamily.UniProtO957861EQUAL925EQUALReactome DB_ID: 89851131OASL:DDX58 [cytosol]OASL:DDX58Reactome DB_ID: 101567811EQUAL514EQUALReactome DB_ID: 16891711EQUAL925EQUALReactome Database ID Release 758985113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985113ReactomeR-HSA-89851131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985113.1Reactome Database ID Release 758985153Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985153ReactomeR-HSA-89851531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985153.121478870Pubmed2011A diverse range of gene products are effectors of the type I interferon antiviral responseSchoggins, John WWilson, Sam JPanis, MarylineMurphy, Mary YJones, Christopher TBieniasz, PaulRice, Charles MNature 472:481-524931123Pubmed2014Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensorZhu, JianzhongZhang, YugenGhosh, ArundhatiCuevas, Rolando AForero, AdrianaDhar, JayeetaIbsen, Mikkel SøesSchmid-Burgk, Jonathan LeoSchmidt, TobiasGanapathiraju, Madhavi KFujita, THartmann, RuneBarik, SailenHornung, VeitCoyne, Carolyn BSarkar, Saumendra NImmunity 40:936-4818931074Pubmed2008The p59 oligoadenylate synthetase-like protein possesses antiviral activity that requires the C-terminal ubiquitin-like domainMarques, JoaoAnwar, JangawarEskildsen-Larsen, SigneRebouillat, DominiquePaludan, SRSen, GanesWilliams, Bryan R GHartmann, RuneJ. Gen. Virol. 89:2767-7215464592Pubmed2004Novel functions of proteins encoded by viral stress-inducible genesSarkar, Saumendra NSen, Ganes CPharmacol. Ther. 103:245-599826176Pubmed1998Molecular cloning and characterization of two related and interferon-induced 56-kDa and 30-kDa proteins highly similar to 2'-5' oligoadenylate synthetaseRebouillat, DMarié, IHovanessian, A GEur. J. Biochem. 257:319-3019203244Pubmed2009Differential regulation of the OASL and OAS1 genes in response to viral infectionsMelchjorsen, JKristiansen, HelleChristiansen, RuneRintahaka, JohannaMatikainen, SampsaPaludan, Søren RHartmann, RuneJ. Interferon Cytokine Res. 29:199-2079722630Pubmed1998p59OASL, a 2'-5' oligoadenylate synthetase like protein: a novel human gene related to the 2'-5' oligoadenylate synthetase familyHartmann, ROlsen, H SWidder, SJorgensen, RJustesen, JNucleic Acids Res. 26:4121-8RNASEL binds 2'-5' oligoadenylateRNASEL binds 2'-5' oligoadenylateRibonuclease L (RNASEL) gene encodes an ankyrin (ANK) repeat domain containing dual endoribonuclease-pseudokinase RNase L that functions in the interferon (IFN) antiviral response (Wreschner DH et al. 1982; Zhou A et al.1993; Hassel BA et al. 1993; Huang H et al. 2014; Han Y et al. 2014). Upon activation by viral double-stranded RNA, 5'-triphosphorylated 2'-5'-linked oligoadenylates (2-5A) are synthesized by one of several 2'-5' oligoadenylate synthetases (OAS). The 2-5A binds to monomeric, inactive RNase L causing it to dimerize through the ANK domains (Dong B & Silverman RH 1995; Tanaka N et al. 2004, 2005; Han Y et al., 2012). Activated RNase L cleaves single-stranded viral and cellular RNA, predominantly after UpU and UpA dinucleotides (Floyd-Smith G et al. 1981; Wreschner DH et al. 1981). The triadenylate form of 2-5A is the minimal active molecule, however, longer 2',5'-oligoadenylates retain the ability to activate RNase L (Dong B et al. 1994).<p>RNase L possesses nine ankyrin repeats (the 9th being incomplete) in the N-terminus, and pseudokinase and nuclease domains in the C-terminus, which is also termed the kinase-extension nuclease (KEN) domain (Hassel BA et al. 1993; Tanaka N et al. 2004; Han Y et al. 2014; Huang H et al. 2014). The monomeric RNase L lacks nucleolytic activity, however, deletion of ankyrin repeats caused constitutive, albeit reduced, ribonuclease activity (Dong B et al. 1997). Crystal structure data indicate that 2-5A binds to the second and fourth ankyrin repeats and the pseudokinase domain (Tanaka N et al. 2004; Huang H et al. 2014; Han Y et al. 2014). These interactions, in conjunction with binding between the pseudokinase domains of the two protomers, mediate dimerization and enzymatic activation within minutes (Huang H et al. 2014; Han Y et al. 2012, 2014). Once active, RNase L cleaves ssRNA, including cellular mRNA and rRNA as well as microbial RNAs. In uninfected cells RNase L interacts with the actin-binding protein filamin A (FLNA) to modulate the actin cytoskeleton and inhibit virus entry into cells (Malathi K et al. 2014; Ezelle HJ et al. 2016). Upon infection and activation of its enzymatic activity by 2-5A, RNase L dissociates from FLNA to mediate its antiviral signaling (Malathi K et al. 2014; Ezelle HJ et al. 2016).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 89836961Reactome DB_ID: 89854082RNASEL:FLNA [cytosol]RNASEL:FLNARNase L:FLNAReactome DB_ID: 10156841UniProt:Q05823 RNASELRNASELRNASELRNS4FUNCTION Endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. In the crosstalk between autophagy and apoptosis proposed to induce autophagy as an early stress response to small double-stranded RNA and at later stages of prolonged stress to activate caspase-dependent proteolytic cleavage of BECN1 to terminate autophagy and promote apoptosis (PubMed:26263979). Might play a central role in the regulation of mRNA turnover (PubMed:11585831). Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length.ACTIVITY REGULATION After binding to 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) the homodimerization and subsequent activation occurs. Inhibited by RNASEL inhibitor ABCE1/RLI, a cytoplasmic member of the ATP-binding cassette (ABC) transporter family.SUBUNIT Monomer (inactive form) or homodimer. Interacts with ABCE1; this interaction inhibits the RNASEL.TISSUE SPECIFICITY Highly expressed in spleen and thymus followed by prostate, testis, uterus, small intestine, colon and peripheral blood leukocytes.INDUCTION By interferons. Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases (OASs). oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNASEL.DOMAIN The nine ankyrin repeats also called 2-5A sensor constitute the N-terminus 2-5A binding domain.DOMAIN The protein kinase domain is predicted to be catalytically inactive. It allows the homodimerization.DOMAIN The ribonuclease domain is located in the C-terminus. A single active nuclease domain in a dimer is sufficient for ribonuclease activity (By similarity).SIMILARITY Belongs to the protein kinase superfamily.UniProtQ058231EQUAL741EQUALReactome DB_ID: 2100191UniProt:P21333 FLNAFLNAFLNAFLNFLN1FUNCTION Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNB may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis. Plays a role in cell-cell contacts and adherens junctions during the development of blood vessels, heart and brain organs. Plays a role in platelets morphology through interaction with SYK that regulates ITAM- and ITAM-like-containing receptor signaling, resulting in by platelet cytoskeleton organization maintenance (By similarity). During the axon guidance process, required for growth cone collapse induced by SEMA3A-mediated stimulation of neurons (PubMed:25358863).SUBUNIT Homodimer. Interacts with PDLIM2 (By similarity). Interacts with RFLNA and RFLNB (By similarity). Interacts with FCGR1A, FLNB, FURIN, HSPB7, INPPL1, KCND2, MYOT, MYOZ1, ARHGAP24, PSEN1, PSEN2 and ECSCR. Interacts also with various other binding partners in addition to filamentous actin. Interacts (via N-terminus) with MIS18BP1 (via N-terminus). Interacts (via N-terminus) with TAF1B. Interacts with TMEM67 (via C-terminus) and MKS1. Interacts (via actin-binding domain) with MICALL2 (via CH domain). Interacts (via filamin repeat 5) with SYK; docks SYK to the plasma membrane (PubMed:20713593). Interacts (via filamin repeats 19 and 21) with DRD3; increased PKA-mediated phosphorylation at Ser-2152. Interacts (via filamin repeat 21) with MAS1, AGTR1 and ADRA1D; increases PKA-mediated phosphorylation of FLNA at Ser-2152 (PubMed:26460884). Interacts (via filamin repeats 4, 9, 12, 17, 19, 21, and 23) with GP1BA (high affinity), ITGB7, ITGB2 and FBLIM1 (PubMed:19828450, PubMed:21524097, PubMed:25666618). Interacts with CEACAM1 (via cytoplasmic domain); inhibits cell migration and cell scattering by interfering with the interaction between FLNA and RALA (PubMed:16291724). Interacts with FOXC1 (PubMed:15684392). Interacts (via calponin-homology (CH) domain 1 and filamin repeat 24) with CRMP1; the interaction alters FLNA ternary structure and thus promotes FLNA dissociation from F-actin (PubMed:25358863). Interacts with DPYSL3/CRMP3 and DPYSL4/CRMP4 (PubMed:25358863).TISSUE SPECIFICITY Ubiquitous.DOMAIN Comprised of a NH2-terminal actin-binding domain, 24 immunoglobulin-like internally homologous repeats and two hinge regions. Repeat 24 and the second hinge domain are important for dimer formation. Filamin repeat 20 interacts with filamin repeat 21 masking the ligand binding site on filamin repeat 21, resulting in an autoinhibited conformation (PubMed:17690686). The autoinhibition can be relieved by ligands like ITGB7 or FBLIM1 (PubMed:21524097). Filamin repeats 19 and 21 can simultaneously engage ligands (PubMed:21524097).PTM Phosphorylation at Ser-2152 is negatively regulated by the autoinhibited conformation of filamin repeats 19-21. Ligand binding induces a conformational switch triggering phosphorylation at Ser-2152 by PKA.PTM Phosphorylation extent changes in response to cell activation.PTM Polyubiquitination in the CH1 domain by a SCF-like complex containing ASB2 leads to proteasomal degradation. Prior dissociation from actin may be required to expose the target lysines (PubMed:24052262). Ubiquitinated in endothelial cells by RNF213 downstream of the non-canonical Wnt signaling pathway, leading to its degradation by the proteasome (PubMed:26766444).DISEASE Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abnormally enlarged (PubMed:21960593).SIMILARITY Belongs to the filamin family.CAUTION Variant Thr-1764 has been originally associated with periventricular nodular heterotopia. It has been subsequently reported as a benign polymorphism.UniProtP213332EQUAL2647EQUALReactome Database ID Release 758985408Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985408ReactomeR-HSA-89854081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985408.1Reactome DB_ID: 89851321RNASEL:2'-5' oligoadenylate [cytosol]RNASEL:2'-5' oligoadenylateReactome DB_ID: 89836961Reactome DB_ID: 101568421EQUAL741EQUALReactome Database ID Release 758985132Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985132ReactomeR-HSA-89851321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985132.1Reactome DB_ID: 21001922EQUAL2647EQUALReactome Database ID Release 758985123Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985123ReactomeR-HSA-89851232Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985123.217150764Pubmed2005Molecular basis for recognition of 2',5'-linked oligoadenylates by the N-terminal ankyrin repeat domain of human ribonuclease LTanaka, NobutadaNakanishi, MasayukiKusakabe, YoshioGoto, YoshikuniKitade, YukioNakamura, Kazuo TNucleic Acids Symp Ser (Oxf)323-415385955Pubmed2004Structural basis for recognition of 2',5'-linked oligoadenylates by human ribonuclease LTanaka, NobutadaNakanishi, MasayukiKusakabe, YoshioGoto, YoshikuniKitade, YukioNakamura, Kazuo TEMBO J. 23:3929-3825352621Pubmed2014RNase L interacts with Filamin A to regulate actin dynamics and barrier function for viral entryMalathi, KrishnamurthySiddiqui, Mohammad AdnanDayal, ShubhamNaji, MernaEzelle, Heather JZeng, ChunZhou, AiminHassel, Bret AMBio 5:e020127514601Pubmed1994Intrinsic molecular activities of the interferon-induced 2-5A-dependent RNaseDong, BXu, LZhou, AHassel, B ALee, XTorrence, P FSilverman, R HJ. Biol. Chem. 269:14153-87876164Pubmed19952-5A-dependent RNase molecules dimerize during activation by 2-5ADong, BSilverman, R HJ. Biol. Chem. 270:4133-723084743Pubmed2012Innate immune messenger 2-5A tethers human RNase L into active high-order complexesHan, YuchenWhitney, GenaDonovan, JesseKorennykh, AlexeiCell Rep 2:902-136284502Pubmed1982Affinity labelling and characterization of the ppp(A2'p)nA-dependent endoribonuclease from different mammalian sourcesWreschner, D HSilverman, R HJames, T CGilbert, C SKerr, I MEur. J. Biochem. 124:261-87680958Pubmed1993Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon actionZhou, AHassel, B ASilverman, R HCell 72:753-657688298Pubmed1993A dominant negative mutant of 2-5A-dependent RNase suppresses antiproliferative and antiviral effects of interferonHassel, B AZhou, ASotomayor, CMaran, ASilverman, R HEMBO J. 12:3297-3046162102Pubmed1981Interferon action--sequence specificity of the ppp(A2'p)nA-dependent ribonucleaseWreschner, DHMcCauley, JWSkehel, JJKerr, IMNature 289:414-726760998Pubmed2016The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate ResponseEzelle, Heather JMalathi, KrishnamurthyHassel, Bret AInt J Mol Sci 17:6165080Pubmed1981Interferon action: RNA cleavage pattern of a (2'-5')oligoadenylate--dependent endonucleaseFloyd-Smith, GSlattery, ELengyel, PScience 212:1030-29268370Pubmed1997A bipartite model of 2-5A-dependent RNase LDong, BSilverman, R HJ. Biol. Chem. 272:22236-42INHIBITIONReactome Database ID Release 759615057Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9615057Reactome DB_ID: 9615046UniProt:B1NKT1 No nameNo nameVP3FUNCTION Multifunctional enzyme involved in mRNA capping. Catalyzes the formation of the 5' cap structure on the viral plus-strand transcripts. Specifically binds to GTP and displays guanylyltransferase and methyltransferase activities. Has affinity for ssRNA but not for dsRNA. Capping activity is non-specific and caps RNAs that initiate with either a G or an A residue. Together with VP1 polymerase, forms a VP1-VP3 complex positioned near the channels situated at each of the five-fold vertices of the core. Following infection, the outermost layer of the virus is lost, leaving a double-layered particle (DLP) made up of the core and VP6 shell. VP1 then catalyzes the transcription of fully conservative plus-strand genomic RNAs that are capped by VP3 and extruded through the DLP's channels into the cytoplasm where they function as mRNAs for translation of viral proteins. DLPs probably have an RNA triphosphatase activity as well, whereas open cores do not.FUNCTION Counteracts the host innate immune response thanks to its phosphodiesterase that degrades the 5'-triphosphorylated, 2'-5' linked adenylate oligomers produced by the host cell IFN-inducible 2',5'-oligoadenylate synthetase (OAS). The host RNaseL is therefore not activated.SUBUNIT Interacts with VP1. Interacts with VP2.DOMAIN Contains a bipartite N7-methytransferase domain, a 2'-O-methytransferase domain and a GTase/RTPase domain. The C-terminus contains a phosphodiesterase domain that degrades the 5'-triphosphorylated, 2'-5' linked adenylate oligomers produced by the host cell in response to IFN stimulation.SIMILARITY Belongs to the rotavirus VP3 family.Rotavirus ANCBI Taxonomy28875UniProtB1NKT11EQUAL835EQUALINHIBITIONReactome Database ID Release 758985570Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985570Reactome DB_ID: 8985572UniProt:Q6L8Q7 PDE12PDE12PDE12FUNCTION Enzyme that cleaves 2',5'-phosphodiester bond linking adenosines of the 5'-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system. Degrades triphosphorylated 2-5A to produce AMP and ATP (PubMed:26055709). Also cleaves 3',5'-phosphodiester bond of oligoadenylates (PubMed:21666256, PubMed:30389976, PubMed:26055709). Plays a role as a negative regulator of the 2-5A system that is one of the major pathways for antiviral and antitumor functions induced by interferons (IFNs). Suppression of this enzyme increases cellular 2-5A levels and decreases viral replication in cultured small-airway epithelial cells and Hela cells (PubMed:26055709).TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the CCR4/nocturin family.UniProtQ6L8Q717EQUAL609EQUALINHIBITIONReactome Database ID Release 758985562Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985562Reactome DB_ID: 8985209UniProt:P61221 ABCE1ABCE1RNS4IRNASELIABCE1OK/SW-cl.40RLIRNASEL1FUNCTION Antagonizes the binding of 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) by RNase L through direct interaction with RNase L and therefore inhibits its endoribonuclease activity. May play a central role in the regulation of mRNA turnover. Antagonizes the anti-viral effect of the interferon-regulated 2-5A/RNase L pathway. May act as a chaperone for post-translational events during HIV-1 capsid assembly.SUBUNIT Probably heterodimerizes with RNASEL; this interaction inhibits the RNASEL.SUBUNIT (Microbial infection) Interacts with HIV-1 proteins Vif and Gag.SUBUNIT (Microbial infection) Interacts with HIV-2 protein Gag.INDUCTION Activated by encephalomyocarditis virus (EMCV) and HIV-1.MISCELLANEOUS The ABC transporter domains seem not to be functional.SIMILARITY Belongs to the ABC transporter superfamily. ABCE family.UniProtP612211EQUAL599EQUALRNASEL cleaves viral ssRNARNASEL cleaves viral ssRNARNASEL cleaves viral ssRNA to generate 5'-OH, 2'-3' cyclic phosphate RNA fragmentsRibonuclease L (RNase L) is an ankyrin (ANK) repeat domain containing dual endoribonuclease-pseudokinase which is encoded by RNASEL gene (Wreschner DH et al. 1982; Zhou A et al.1993; Hassel BA et al. 1993; Huang H et al. 2014; Han Y et al. 2014). Activated RNase L forms a homodimer (Dong B & Silverman RH 1995) which cleaves within single-stranded regions of different RNA substrates, predominantly after UpAp and UpUp dinucleotides, leaving 2',3'-cyclic phosphoryl and 5'-hydroxyl groups at the termini of the RNA cleavage products (Wreschner DH et al. 1981; Floyd-Smith G et al. 1981; Han Y et al. 2012; Cooper DA et al. 2014). The antiviral effect of RNase L occurs through a combination of effects and depends on the virus and cell type. This includes cleavage of viral genomic ssRNA that prevents viral replication (Cooper DA et al. 2015), cleavage of viral mRNA that inhibits viral protein synthesis, and cleavage of cellular RNA such as mRNA and rRNA that is required for viral replication (Wreschner DH et al. 1981; Silverman RH et al.1983; Brennan-Laun SE et al. 2014; Cooper DA et al. 2014). RNase L induces apoptosis to eliminate virus-infected cells and autophagy to limit viral infections in some circumstances (Zhou A et al. 1997; Castelli JC et al. 1997; Chakrabarti A et al. 2012). Depending on the cell type and basal levels of RNase L, viral and cellular RNA cleavage products induce signaling to the IFN beta gene through RIG-I and/or MDA5 and MAVS (Malathi K et al. 2007; Banerjee S et al. 2014).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 90099661FLUAV UpN-ssRNA [cytosol]FLUAV UpN-ssRNAReactome DB_ID: 90099451RNA fragment with 2'-3' cyclic phosphate [cytosol]RNA fragment with 2'-3' cyclic phosphate PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8985132GO0004521GO molecular functionReactome Database ID Release 759009939Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9009939Reactome Database ID Release 759009941Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9009941ReactomeR-HSA-90099411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9009941.16164990Pubmed1981Ribosomal RNA cleavage, nuclease activation and 2-5A(ppp(A2'p)nA) in interferon-treated cellsWreschner, D HJames, T CSilverman, R HKerr, I MNucleic Acids Res. 9:1571-819351818Pubmed1997Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase LZhou, AParanjape, JBrown, T LNie, HNaik, SDong, BChang, ATrapp, BFairchild, RColmenares, CSilverman, R HEMBO J. 16:6355-6325540362Pubmed2015RNase L targets distinct sites in influenza A virus RNAsCooper, Daphne ABanerjee, ShuvojitChakrabarti, ArindamGarcía-Sastre, AdolfoHesselberth, Jay RSilverman, Robert HBarton, David JJ. Virol. 89:2764-7622875977Pubmed2012RNase L triggers autophagy in response to viral infectionsChakrabarti, ArindamGhosh, Prabar KumarBanerjee, ShuvojitGaughan, ChristinaSilverman, Robert HJ. Virol. 86:11311-2124697205Pubmed2014RNase-L control of cellular mRNAs: roles in biologic functions and mechanisms of substrate targetingBrennan-Laun, Sarah EEzelle, Heather JLi, Xiao-LingHassel, Bret AJ. Interferon Cytokine Res. 34:275-8824500209Pubmed2014Ribonuclease L and metal-ion-independent endoribonuclease cleavage sites in host and viral RNAsCooper, Daphne AJha, Babal KSilverman, Robert HHesselberth, Jay RBarton, David JNucleic Acids Res. 42:5202-1624570368Pubmed2014Cell-type-specific effects of RNase L on viral induction of beta interferonBanerjee, ShuvojitChakrabarti, ArindamJha, Babal KantWeiss, Susan RSilverman, Robert HMBio 5:e00856-149294150Pubmed1997A study of the interferon antiviral mechanism: apoptosis activation by the 2-5A systemCastelli, J CHassel, B AWood, K ALi, X LAmemiya, KDalakas, M CTorrence, P FYoule, R JJ. Exp. Med. 186:967-726190010Pubmed1983rRNA cleavage as an index of ppp(A2'p)nA activity in interferon-treated encephalomyocarditis virus-infected cellsSilverman, R HSkehel, J JJames, T CWreschner, D HKerr, I MJ. Virol. 46:1051-517653195Pubmed2007Small self-RNA generated by RNase L amplifies antiviral innate immunityMalathi, KrishnamurthyDong, BeihuaGale, MichaelSilverman, Robert HNature 448:816-9RNASEL cleaves cellular ssRNARNASEL cleaves cellular ssRNARNASEL cleaves cellular ssRNA to generate 5'-OH, 2'-3' cyclic phosphate RNA fragmentsRibonuclease L (RNase L) is an ankyrin (ANK) repeat domain containing dual endoribonuclease-pseudokinase which is encoded by RNASEL gene (Wreschner DH et al. 1982; Zhou A et al.1993; Hassel BA et al. 1993; Huang H et al. 2014; Han Y et al. 2014). Activated RNase L forms a homodimer (Dong B & Silverman RH 1995) which cleaves within single-stranded regions of different RNA substrates, predominantly after UpAp and UpUp dinucleotides, leaving 2',3'-cyclic phosphoryl and 5'-hydroxyl groups at the termini of the RNA cleavage products (Wreschner DH et al. 1981; Floyd-Smith G et al. 1981; Han Y et al. 2012; Cooper DA et al. 2014). The antiviral function of RNase L extends beyond direct cleavage of viral RNA and includes also cleavage of cellular RNA such as mRNA and rRNA that is required for viral replication (Wreschner DH et al. 1981; Silverman RH et al.1983; Brennan-Laun SE et al. 2014; Cooper DA et al. 2014). RNase L induces apoptosis to eliminate virus-infected cells and autophagy to limit viral infections in some circumstances (Zhou A et al. 1997; Castelli JC et al. 1997; Chakrabarti A et al. 2012). Depending on the cell type and basal levels of RNase L, viral and cellular RNA cleavage products induce signaling to the IFN beta gene through RIG-I and/or MDA5 and MAVS (Malathi K et al. 2007; Banerjee S etl al. 2014).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 1702921ssRNA [cytosol]ssRNAReactome DB_ID: 90099451PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8985132Reactome Database ID Release 759009936Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9009936ReactomeR-HSA-90099361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9009936.1ABCE1 binds RNASELABCE1 binds RNASELATP-binding cassette sub-family E member 1 (ABCE1, aka RNase L inhibitor, RLI) is a member of the ATP-binding cassette transporters which express in the cytoplasm and the nuclear membrane. ABCE1 is induced during viral infections (Bisbal C et al. 1995; Martinand C et al. 1998, 1999). ABCE1 (RLI) was shown to associate with RNase L inhibiting the endoribonuclease activity of RNase L, thus antagonising the anti-viral effect of the IFN-regulated 2'-5' oligoadenylate/RNase L pathway (Bisbal C et al. 1995; Martinand C et al. 1998, 1999). Furthermore, overexpression or knockdown of ABCE1 (RLI) has inhibitory or promoting effects on the binding of RNase L to 2'-5' oligoadenylates, rRNA cleavage, destabilization of mitochondrial mRNA, antiviral activity, and antitumor activity (Martinand C et al. 1998, 1999; Le Roy F et al. 2001; Malathi K et al. 2004; Huang B et al. 2014; Tian Y et al. 2016). Aside from its role as an RNase-L inhibitor, ABCE1 is believed to be involved in translation termination and ribosome recycling (Dong J et al. 2004; Chen ZQ et al. 2006; Khoshnevis S et al. 2010).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 898520911EQUAL599EQUALReactome DB_ID: 101568411EQUAL741EQUALReactome DB_ID: 89852051ABCE1:RNASEL [cytosol]ABCE1:RNASELReactome DB_ID: 898520911EQUAL599EQUALReactome DB_ID: 101568411EQUAL741EQUALReactome Database ID Release 758985205Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985205ReactomeR-HSA-89852051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985205.1Reactome Database ID Release 758985201Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8985201ReactomeR-HSA-89852011Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8985201.17539425Pubmed1995Cloning and characterization of a RNAse L inhibitor. A new component of the interferon-regulated 2-5A pathwayBisbal, CMartinand, CSilhol, MLebleu, BSalehzada, TJ. Biol. Chem. 270:13308-1720062004Pubmed2010The iron-sulphur protein RNase L inhibitor functions in translation terminationKhoshnevis, SohailGross, ThomasRotte, CarmenBaierlein, ClaudiaFicner, RalfKrebber, HeikeEMBO Rep. 11:214-925070080Pubmed2014siRNA‑induced ABCE1 silencing inhibits proliferation and invasion of breast cancer cellsHuang, BoZhou, HongliLang, XianpingLiu, ZhiliangMol Med Rep 10:1685-909847332Pubmed1999RNase L inhibitor is induced during human immunodeficiency virus type 1 infection and down regulates the 2-5A/RNase L pathway in human T cellsMartinand, CMontavon, CSalehzada, TSilhol, MLebleu, BBisbal, CJ. Virol. 73:290-611585831Pubmed2001The 2-5A/RNase L/RNase L inhibitor (RLI) [correction of (RNI)] pathway regulates mitochondrial mRNAs stability in interferon alpha-treated H9 cellsLe Roy, FBisbal, CSilhol, MMartinand, CLebleu, BSalehzada, TJ. Biol. Chem. 276:48473-8227314749Pubmed2016Expression of ATP binding cassette E1 enhances viability and invasiveness of lung adenocarcinoma cells in vitroTian, YeTian, XinHan, XuChen, YongSong, Cheng-YangZhang, Yan-BinTian, Da-LiMol Med Rep 14:1345-509660177Pubmed1998RNase L inhibitor (RLI) antisense constructions block partially the down regulation of the 2-5A/RNase L pathway in encephalomyocarditis-virus-(EMCV)-infected cellsMartinand, CSalehzada, TSilhol, MLebleu, BBisbal, CEur. J. Biochem. 254:248-5516421098Pubmed2006The essential vertebrate ABCE1 protein interacts with eukaryotic initiation factorsChen, Zhang-QunDong, JinshengIshimura, AkihikoDaar, IraHinnebusch, Alan GDean, MichaelJ. Biol. Chem. 281:7452-715277527Pubmed2004The essential ATP-binding cassette protein RLI1 functions in translation by promoting preinitiation complex assemblyDong, JinshengLai, RubyNielsen, KlausFekete, Christie AQiu, HongfangHinnebusch, Alan GJ. Biol. Chem. 279:42157-6815604285Pubmed2004HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligandMalathi, KrishnamurthyParanjape, Jayashree MGanapathi, RamSilverman, Robert HCancer Res. 64:9144-5111265282Pubmed2001The 2-5A/RNase L pathway and inhibition by RNase L inhibitor (RLI)Bisbal, CSalehzada, TSilhol, MMartinand, CLe Roy, FLebleu, BMethods Mol. Biol. 160:183-98PDE12 cleaves 2'-5' oligoadenylates PDE12 cleaves 2'-5' oligoadenylates Viral infection produces dsRNA that activates OAS isozymes to synthesize 5'-triphosphorylated 2'-5'-linked oligoadenylate (2-5A). Latent ribonuclease L (RNase L) binds 2-5A and oligomerizes into an active complex capable of cleaving ssRNA into retinoic acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome-activating small RNAs (Malathi K et al. 2007; Chakrabarti A et al. 2015). Activation of RNase L can be attenuated by 2′-phosphodiesterase (PDE12)- mediated degradation of 2-5A. PDE12 is an endonuclease/exonuclease/phosphatase family member of deadenylases with both 3’,5’- and 2’,5’-phosphodiesterase activities. PDE12 localizes to the mitochondrial matrix and, in addition to degrading 2-5A, removes poly(A) tails from some mitochondrial mRNAs (Kubota K et al. 2004; Poulsen JB et al. 2011; Rorbach J et al. 2011; Silverman RH & Weiss SR 2014; Wood ER et al. 2015). The 2H phosphoesterase, AKAP7, is an unrelated nuclear enzyme that also degrades 2-5A (Gusho E et al. 2014). Several viruses, including some coronaviruses and rotaviruses, encode structurally related 2H phosphoesterases (each with two conserved histidine motifs) that degrade 2-5A and antagonize RNase L mediated antiviral activity (Zhao L et al. 2012; Zhang R et al. 2013; Silverman RH & Weiss SR 2014; Ogden KM et al. 2015; Sui B et al. 2016; Thornbrough JM et al. 2016; Goldstein SA et al. 2017).Authored: Shamovsky, Veronica, 2017-03-27Reviewed: D'Eustachio, Peter, 2017-12-01Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 89836961Reactome DB_ID: 293561water [ChEBI:15377]waterChEBI15377Reactome DB_ID: 765771Reactome DB_ID: 1135921Reactome DB_ID: 701061hydron [ChEBI:15378]hydronChEBI15378PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 898557217EQUAL609EQUALGO0034611GO molecular functionReactome Database ID Release 759009951Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9009951Reactome Database ID Release 759009950Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9009950ReactomeR-HSA-90099501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9009950.115231837Pubmed2004Identification of 2'-phosphodiesterase, which plays a role in the 2-5A system regulated by interferonKubota, KazuishiNakahara, KaoriOhtsuka, ToshiakiYoshida, ShukuKawaguchi, JunkoFujita, YokoOzeki, YoheiHara, AyakoYoshimura, ChigusaFurukawa, HidehikoHaruyama, HideyukiIchikawa, KimihisaYamashita, MakotoMatsuoka, TatsujiIijima, YasuteruJ. Biol. Chem. 279:37832-4126757803Pubmed2016Crystal structure of the mouse hepatitis virus ns2 phosphodiesterase domain that antagonizes RNase L activationSui, BaokunHuang, JunhuaJha, Babal KYin, PingZhou, MingFu, Zhen FSilverman, Robert HWeiss, Susan RPeng, GuiqingZhao, LingJ. Gen. Virol. 97:880-626055709Pubmed2015The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral InhibitorsWood, Edgar RBledsoe, RandyChai, JingDaka, PhiliasDeng, HongfengDing, YunHarris-Gurley, SarahKryn, Luz HelenaNartey, EldridgeNichols, JamesNolte, Robert TPrabhu, NinadRise, CecilSheahan, TimothyShotwell, J BradSmith, DanielleTai, VinceTaylor, J DavidTomberlin, GingerWang, LipingWisely, BruceYou, ShihyunXia, BingDickson, HamiltonJ. Biol. Chem. 290:19681-9621666256Pubmed2011PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondriaRorbach, JoannaNicholls, Thomas J JMinczuk, MichalNucleic Acids Res. 39:7750-6324987090Pubmed2014Murine AKAP7 has a 2',5'-phosphodiesterase domain that can complement an inactive murine coronavirus ns2 geneGusho, ElonaZhang, RongJha, Babal KThornbrough, Joshua MDong, BeihuaGaughan, ChristinaElliott, RuthWeiss, Susan RSilverman, Robert HMBio 5:e01312-1427025250Pubmed2016Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L ActivationThornbrough, Joshua MJha, Babal KYount, BoydGoldstein, Stephen ALi, YizeElliott, RuthSims, Amy CBaric, Ralph SSilverman, Robert HWeiss, Susan RMBio 7:e0025825878106Pubmed2015Structural basis for 2'-5'-oligoadenylate binding and enzyme activity of a viral RNase L antagonistOgden, Kristen MHu, LiyaJha, Babal KSankaran, BanumathiWeiss, Susan RSilverman, Robert HPatton, John TPrasad, B V VenkataramJ. Virol. 89:6633-4522704621Pubmed2012Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathologyZhao, LingJha, Babal KWu, AshleyElliott, RuthZiebuhr, JohnGorbalenya, Alexander ESilverman, Robert HWeiss, Susan RCell Host Microbe 11:607-1628003490Pubmed2017Lineage A Betacoronavirus NS2 Proteins and the Homologous Torovirus Berne pp1a Carboxy-Terminal Domain Are Phosphodiesterases That Antagonize Activation of RNase LGoldstein, Stephen AThornbrough, Joshua MZhang, RongJha, Babal KLi, YizeElliott, RuthQuiroz-Figueroa, KatherineChen, Annie ISilverman, Robert HWeiss, Susan RJ. Virol. 91:21245038Pubmed2011Human 2'-phosphodiesterase localizes to the mitochondrial matrix with a putative function in mitochondrial RNA turnoverPoulsen, Jesper BuchhaveAndersen, Kasper RøjkjærKjær, Karina HansenDurand, FionaFaou, PierreVestergaard, Anna LindeløvTalbo, Gert HoyHoogenraad, NickBrodersen, Ditlev EgeskovJustesen, JMartensen, Pia MøllerNucleic Acids Res. 39:3754-7023878220Pubmed2013Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunityZhang, RongJha, Babal KOgden, Kristen MDong, BeihuaZhao, LingElliott, RuthPatton, John TSilverman, Robert HWeiss, Susan RProc. Natl. Acad. Sci. U.S.A. 110:13114-925816776Pubmed2015RNase L activates the NLRP3 inflammasome during viral infectionsChakrabarti, ArindamBanerjee, ShuvojitFranchi, LuigiLoo, Yueh-MingGale, MichaelNúñez, GabrielSilverman, Robert HCell Host Microbe 17:466-7724905202Pubmed2014Viral phosphodiesterases that antagonize double-stranded RNA signaling to RNase L by degrading 2-5ASilverman, Robert HWeiss, Susan RJ. Interferon Cytokine Res. 34:455-63Viral 2',5'-PDE cleaves 2'-5' oligoadenylates Viral 2',5'-PDE cleaves 2'-5' oligoadenylates Viral infection produces dsRNA that activates the 2'-5' oligoadenylate synthetase (OAS) to synthesize 5'-triphosphorylated 2'-5'-linked oligoadenylate from ATP. The 2'-5'-linked oligoadenylate with a chemical structure of ppp5'A(2'p5'A)n contain 2 to greater than 5 adenylyl residues (n>2) and are commonly referred to as 2-5A (Kerr IM & Brown RE 1978). The 2-5As bind latent ribonuclease L (RNase L) which in human is encoded by RNASEL gene. RNase L oligomerizes into an active complex capable of cleaving viral ssRNA and cellular ssRNA to inhibit viral replication and spread (Silverman RH 2007; Malathi K et al. 2007; Chakrabarti A et al. 2015). Viruses have developed diverse strategies to escape the host antiviral effects. Several viruses, including some coronaviruses and rotaviruses, encode structurally related 2H phosphoesterases with two conserved His-x-Ser/Thr motifs in their catalytic sites. The NS4b protein of Middle East respiratory syndrome coronavirus (MERS-CoV), the protein VP3 of rotavirus A (RVA), the non-structural 2 (NS2) protein of human respiratory coronavirus HCoV-OC43 and its homologue ns2 protein of mouse hepatitis virus (MHV) possess enzymatic 2′,5-phosphodiesterase (PDE) activity that is capable of antagonizing RNase L and thus countering a potent host antiviral response in mammals (Mazumder R et al., 2002; Zhao L et al. 2012; Zhang R et al. 2013; Silverman RH & Weiss SR 2014; Ogden KM et al. 2015; Sui B et al. 2016; Thornbrough JM et al. 2016; Goldstein SA et al. 2017). The viral 2',5'-PDEs are phylogenetically related to the cellular 2',5'-PDE, a kinase anchoring protein 7 (AKAP7) (Mazumder R et al., 2002; Gold MG et al. 2008; Ogden KM et al. 2015; Brandmann T & Jinek M 2015). Murine AKAP7 was found to cleave the phosphodiester bonds of 2-5A in vitro with rates similar to its viral homologues, ns2 of MHV and VP3 of RVA (Gusho E et al. 2014). Murine AKAP7 (full length and central domain) also effectively degraded 2-5A in intact pIC-transfected human ovarian carcinoma Hey1B cells (Gusho E et al. 2014). The proviral effect of murine AKAP7 required cytoplasmic localization of the PDE domain of AKAP7, whereas full-length AKAP7 was observed only in nuclei. Further studies are needed to identify the subcellular compartment of 2′,5′-PDE activity of AKAP7.<p>The Reactome event shows a cleavage of 2-5A by RVA protein VP3 as an example of viral 2',5'-PDE activity that antagonizes dsRNA signaling to RNase L.Authored: Shamovsky, Veronica, 2018-07-27Reviewed: Silverman, Robert H, 2018-07-31Edited: Shamovsky, Veronica, 2018-07-31Reactome DB_ID: 89836961Reactome DB_ID: 293561Reactome DB_ID: 765771Reactome DB_ID: 1135921Reactome DB_ID: 701061PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 96150461EQUAL835EQUALReactome Database ID Release 759615048Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9615048Reactome Database ID Release 759615042Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9615042ReactomeR-HSA-96150423Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9615042.318082768Pubmed2008AKAP18 contains a phosphoesterase domain that binds AMPGold, Matthew GSmith, F DonelsonScott, John DBarford, DavidJ. Mol. Biol. 375:1329-4312466548Pubmed2002Detection of novel members, structure-function analysis and evolutionary classification of the 2H phosphoesterase superfamilyMazumder, RajaIyer, Lakshminarayan MVasudevan, SonaAravind, LNucleic Acids Res. 30:5229-4325758703Pubmed2015Crystal structure of the C-terminal 2',5'-phosphodiesterase domain of group A rotavirus protein VP3Brandmann, TobiasJinek, MartinProteins 83:997-1002Reactome Database ID Release 758983711Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8983711ReactomeR-HSA-89837112Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983711.219075243Pubmed2008An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunityLi, Xiao-LingEzelle, Heather JKang, Tae-JinZhang, LeiShirey, Kari AnnHarro, JanetteHasday, Jeffrey DMohapatra, Saroj KCrasta, Oswald RVogel, Stefanie NCross, Alan SHassel, Bret AProc. Natl. Acad. Sci. U.S.A. 105:20816-2125676874Pubmed2015OASL-a new player in controlling antiviral innate immunityZhu, JianzhongGhosh, ArundhatiSarkar, Saumendra NCurr Opin Virol 12:15-918575461Pubmed2008Interferon-inducible antiviral effectorsSadler, AJWilliams, BRNat Rev Immunol 8:559-6819923450Pubmed2009Distinct antiviral roles for human 2',5'-oligoadenylate synthetase family members against dengue virus infectionLin, Ren-JyeYu, Han-PangChang, Bi-LanTang, Wei-ChunLiao, Ching-LenLin, Yi-LingJ. Immunol. 183:8035-4312080145Pubmed2002Positional cloning of the murine flavivirus resistance genePerelygin, Andrey AScherbik, Svetlana VZhulin, Igor BStockman, Bronislava MLi, YBrinton, Margo AProc. Natl. Acad. Sci. U.S.A. 99:9322-7GO0051607GO biological processReactome Database ID Release 751169410Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1169410ReactomeR-HSA-11694104Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169410.4