BioPAX pathway converted from "TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling" in the Reactome database. TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling In plasmacytoid dendritic cell induction of type I IFNs critically depends on IFN regulatory factor 7 in TLR7 and 9 signaling (Honda et al 2005). IRF-7, but not IRF3, interacts with MyD88, TRAF6, and IRAKs and translocates to the nucleus upon phosphorylation (Kawai et al 2004; Uematsu et al 2005).<p> TLR7/8 signaling was shown to induce IRF5 activation along with IRF7 [Schoenemeyer et al 2005], while IRF8 [Tsujimura H et al 2004] and IRF1 were reported to be implicated in TLR9 signaling. Authored: Shamovsky, V, 2010-08-25 Reviewed: Gillespie, ME, 2010-10-29 Edited: Shamovsky, V, 2010-11-15 TRAF6 interacts with IRF7 upon TLR7/8 or 9 activation TRAF6 interacts with IRF7 upon TLR7/8 or 9 activation Upon TLR7/8 or 9 stimulation IRF7, but not IRF3, forms a signaling complex with MyD88, TRAF6[Honda K et al 2004, Kawai T et al 2004], IRAK1 [Uematsu S et al 2005], Also IRAK4 was shown to mediate IRF7 activation[Honda K et al 2004]. Authored: Shamovsky, V, 2010-08-25 Reviewed: Gillespie, ME, 2010-10-29 Edited: Shamovsky, V, 2010-11-15 Reactome DB_ID: 450281 4 cytosol GO 0005829 UniProt:Q92985 IRF7 IRF7 IRF7 FUNCTION Key transcriptional regulator of type I interferon (IFN)-dependent immune responses and plays a critical role in the innate immune response against DNA and RNA viruses. 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:17574024, PubMed:32972995). Can efficiently activate both the IFN-beta (IFNB) and the IFN-alpha (IFNA) genes and mediate their induction via both the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Induces transcription of ubiquitin hydrolase USP25 mRNA in response to lipopolysaccharide (LPS) or viral infection in a type I IFN-dependent manner (By similarity). Required during both the early and late phases of the IFN gene induction but is more critical for the late than for the early phase. Exists in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, becomes phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization where along with other coactivators it can activate transcription of the type I IFN and ISG genes. Can also play a role in regulating adaptive immune responses by inducing PSMB9/LMP2 expression, either directly or through induction of IRF1. Binds to the Q promoter (Qp) of EBV nuclear antigen 1 a (EBNA1) and may play a role in the regulation of EBV latency. Can activate distinct gene expression programs in macrophages and regulate the anti-tumor properties of primary macrophages (By similarity) (PubMed:11073981, PubMed:12374802, PubMed:15361868, PubMed:17404045).ACTIVITY REGULATION In the absence of viral infection, maintained as a monomer in an autoinhibited state and phosphorylation 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.SUBUNIT Monomer. Homodimer; phosphorylation-induced. Heterodimer with IRF3 (PubMed:17574024). Interacts with TICAM1 and TICAM2. Interacts with MYD88 and TRAF6. Interacts with TRIM35 (PubMed:25907537, PubMed:11073981, PubMed:11314014, PubMed:14517278, PubMed:14739303, PubMed:15361868, PubMed:15492225). Interacts with NMI; the interaction is direct and leads to the inhibition of IRF7-mediated type I IFN production (By similarity).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus LF2 and LMP1.SUBUNIT (Microbial infection) Interacts with rotavirus A NSP1; this interaction leads to the proteasome-dependent degradation of IRF7.SUBUNIT (Microbial infection) Interacts with human herpes virus 8/HHV-8 proteins ORF45 and vIRF-1.SUBUNIT (Microbial infection) Interacts with human T-cell leukemia virus 1/HTLV-1 protein HBZ.SUBUNIT (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction is involved in the suppression of IRF7 expression and phosphorylation by the virus.SUBUNIT (Microbial infection) Interacts with ebolavirus VP35; this interaction mediates the sumoylation of IRF7 and contributes to the viral inhibition of IFN-type I production.TISSUE SPECIFICITY Expressed predominantly in spleen, thymus and peripheral blood leukocytes.INDUCTION By type I interferon (IFN) and viruses.PTM Acetylation inhibits its DNA-binding ability and activity.PTM In response to a viral infection, phosphorylated on Ser-477 and Ser-479 by TBK1 and IKBKE1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein E3. In TLR7- and TLR9-mediated signaling pathway, phosphorylated by IRAK1.PTM TRAF6-mediated ubiquitination is required for IRF7 activation (By similarity). TRIM35 mediates IRF7 'Lys-48'-linked polyubiquitination and subsequent proteasomal degradation (PubMed:25907537). Ubiquitinated by UBE3C, leading to its degradation (PubMed:21167755).PTM Sumoylated by TRIM28, which inhibits its transactivation activity.PTM (Microbial infection) Cleaved and inactivated by the protease 3C of enterovirus 71 allowing the virus to disrupt the host type I interferon production.PTM (Microbial infection) Cleaved and inactivated by the protease 3C of human enterovirus 68D (EV68) allowing the virus to disrupt the host type I interferon production.PTM 'Lys-48'-linked polyubiquitination and subsequent proteasomal degradation is NMI-dependent in response to Sendai virus infection.SIMILARITY Belongs to the IRF family. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt Q92985 Chain Coordinates 1 EQUAL 503 EQUAL Reactome DB_ID: 975148 1 endosome membrane GO 0010008 TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 [endosome membrane] TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 Reactome DB_ID: 450272 4 UniProt:Q9Y4K3 TRAF6 TRAF6 TRAF6 RNF85 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2 (PubMed:11057907, PubMed:18347055, PubMed:19713527, PubMed:19465916). Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (PubMed:19675569). Leads to the activation of NF-kappa-B and JUN (PubMed:16378096, PubMed:17135271). Seems to also play a role in dendritic cells (DCs) maturation and/or activation (By similarity). Represses c-Myb-mediated transactivation, in B-lymphocytes (PubMed:18093978, PubMed:18758450). Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:8837778, PubMed:19825828, PubMed:12140561). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (By similarity). Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TANK; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with USP10; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (PubMed:25861989). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (PubMed:28087809). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (PubMed:23776175). Interacts with LRRC19 (PubMed:25026888). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (PubMed:20628368). Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (PubMed:23524951).TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828). Polyubiquitinated on Lys-124; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989). LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt Q9Y4K3 1 EQUAL 522 EQUAL Reactome DB_ID: 975107 1 p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 [endosome membrane] p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 Reactome DB_ID: 975159 1 p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptor [endosome membrane] p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 receptor Reactome DB_ID: 975149 4 UniProt:Q9NWZ3 IRAK4 IRAK4 IRAK4 FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways (PubMed:17878374). Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.SUBUNIT Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome (PubMed:16951688, PubMed:24316379). Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation (PubMed:11960013, PubMed:12496252, PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (PubMed:16951688). Interacts with IL1RL1 (PubMed:16286016). Interacts (when phosphorylated) with IRAK1 (PubMed:33238146). May interact (when phosphorylated) with IRAK3 (PubMed:33238146).PTM Phosphorylated.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. UniProt Q9NWZ3 O-phospho-L-threonine at 342 342 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 345 345 EQUAL O-phospho-L-serine at 346 346 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 460 EQUAL Reactome DB_ID: 975114 1 oligo-MyD88:activated TLR7-9 [endosome membrane] oligo-MyD88:activated TLR7-9 Reactome DB_ID: 975141 1 MyD88 oligomer [endosome membrane] MyD88 oligomer Reactome DB_ID: 975123 6 UniProt:Q99836 MYD88 MYD88 MYD88 FUNCTION Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575, PubMed:33718825). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. Upon TLR8 activation by GU-rich single-stranded RNA (GU-rich RNA) derived from viruses such as SARS-CoV-2, SARS-CoV and HIV-1, induces IL1B release through NLRP3 inflammasome activation (PubMed:33718825). MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).SUBUNIT Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, TLR5, IRAK1, IRAK2 and IRAK4 via their respective TIR domains. Interacts with IL18R1. Interacts with BMX, IL1RL1, IKBKE and IRF7. Interacts with LRRFIP1 and LRRFIP2; this interaction positively regulates Toll-like receptor (TLR) signaling in response to agonist. Interacts with FLII. LRRFIP1 and LRRFIP2 compete with FLII for MYD88-binding. Interacts with IRF1. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and TRAF6; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. May interact with PIK3AP1. Interacts (via TIR domain) with DHX9 (via H2A and OB-fold regions); this interaction is direct (PubMed:20696886). Interacts with OTUD4 deubiquitinase; the interaction is direct (PubMed:29395066).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC; suppressing Toll-like receptor (TLR)-mediated cytokine production.SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.faecalis protein TcpF; suppressing Toll-like receptor (TLR)-mediated cytokine production.TISSUE SPECIFICITY Ubiquitous.DOMAIN The intermediate domain (ID) is required for the phosphorylation and activation of IRAK.PTM Ubiquitinated; undergoes 'Lys-63'-linked polyubiquitination. OTUD4 specifically hydrolyzes 'Lys-63'-linked polyubiquitinated MYD88.DISEASE Defects in MYD88 are frequently found in many hematological malignancies, such as activated B-cell type diffuse large B-cell lymphoma (ABC-DLBCL), cutaneous diffuse large B cell lymphoma (CBCL) and primary central nervous system lymphoma (PCNSL). UniProt Q99836 1 EQUAL 296 EQUAL Reactome Database ID Release 81 975141 Database 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=975141 Reactome R-HSA-975141 1 Reactome 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-975141.1 Converted from EntitySet in Reactome Reactome DB_ID: 975158 1 Activated TLR7-9 homodimers [endosome membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 975114 Database 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=975114 Reactome R-HSA-975114 3 Reactome 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-975114.3 Reactome Database ID Release 81 975159 Database 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=975159 Reactome R-HSA-975159 3 Reactome 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-975159.3 Reactome DB_ID: 975157 4 UniProt:P51617 IRAK1 IRAK1 IRAK IRAK1 FUNCTION Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.SUBUNIT Homodimer (By similarity). Forms a complex with TRAF6, PELI1, IRAK4 and MYD88 (PubMed:16951688). Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression (PubMed:16951688). The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation (PubMed:16951688). Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex (PubMed:9430229). Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation (PubMed:10854325). Interacts with IL1RL1 (PubMed:16286016). Interacts with PELI1 and TRAF6 (PubMed:12496252). Interacts (when polyubiquitinated) with IKBKG/NEMO (PubMed:18347055). Interacts with RSAD2/viperin (By similarity). Interacts with IRAK1BP1 (By similarity). Interacts with PELI2 (By similarity). Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB (By similarity). Interacts with IRAK4 (PubMed:11960013). Interacts with PELI3 (PubMed:12874243). Interacts with INAVA; the interaction takes place upon PRR stimulation (PubMed:28436939). Interacts (via C-terminus) with NFATC4 (via N-terminus) (PubMed:18691762).SUBUNIT (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.SUBUNIT (Microbial infection) Interacts with alphaviruses SINV, CHIKV, RRV, VEEV and EEEV capsid proteins; the interactions lead to inhibition of IRAK1-dependent signaling.TISSUE SPECIFICITY Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.DOMAIN The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation.PTM Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity.PTM Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through 'Lys-63'. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation.SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily. UniProt P51617 O-phospho-L-threonine at 387 387 EQUAL O-phospho-L-serine at 376 376 EQUAL O-phospho-L-threonine at 209 209 EQUAL O-phospho-L-serine at unknown position O-phospho-L-serine at unknown position O-phospho-L-threonine at unknown position 1 EQUAL 712 EQUAL Reactome Database ID Release 81 975107 Database 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=975107 Reactome R-HSA-975107 3 Reactome 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-975107.3 Reactome Database ID Release 81 975148 Database 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=975148 Reactome R-HSA-975148 3 Reactome 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-975148.3 Reactome DB_ID: 975131 1 IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 [endosome membrane] IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9 Reactome DB_ID: 450274 4 1 EQUAL 503 EQUAL Reactome DB_ID: 975148 1 Reactome Database ID Release 81 975131 Database 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=975131 Reactome R-HSA-975131 3 Reactome 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-975131.3 Reactome Database ID Release 81 975188 Database 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=975188 Reactome R-HSA-975188 3 Reactome 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-975188.3 15361868 Pubmed 2004 Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6 Kawai, T Sato, S Ishii, KJ Coban, C Hemmi, H Yamamoto, M Terai, K Matsuda, M Inoue, J Uematsu, S Takeuchi, O Akira, Shizuo Nat Immunol 5:1061-8 15767370 Pubmed 2005 Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction Uematsu, S Sato, S Yamamoto, M Hirotani, T Kato, H Takeshita, F Matsuda, M Coban, C Ishii, KJ Kawai, T Takeuchi, O Akira, Shizuo J Exp Med 201:915-23 15492225 Pubmed 2004 Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling Honda, K Yanai, H Mizutani, T Negishi, H Shimada, N Suzuki, N Ohba, Y Takaoka, A Yeh, WC Taniguchi, T Proc Natl Acad Sci U S A 101:15416-21 6.3.2.19 TRAF6 ubiquitinqtes IRF7 within the activated TLR7/8 or 9 complex TRAF6 ubiquitinqtes IRF7 within the activated TLR7/8 or 9 complex TRAF6 E3 ubiquitin ligase activity was shown to be essential for IRF7 activation, although the role of TRAF6-dependent ubiquitination remains unclear [Kawai T et al 2004]. It has been demonstrated that IRF7 is ubiquitinated by TRAF6 at multiple sites both in vitro and in vivo[Ning et al 2008].It has been also shown that K63-linked ubiquitination of IRF7 is independent of its C-terminal functional phosphorylation sites. Authored: Shamovsky, V, 2010-08-25 Reviewed: Gillespie, ME, 2010-10-29 Edited: Shamovsky, V, 2010-11-15 Reactome DB_ID: 202463 1 UBE2N:UBE2V1 [cytosol] UBE2N:UBE2V1 Ubc13:UBE2V1 TRIKA1 TRAF6-regulated IKK activator 1 Reactome DB_ID: 206072 1 UniProt:P61088 UBE2N UBE2N UBE2N BLU FUNCTION The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UB2V1, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (PubMed:28469175, PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.ACTIVITY REGULATION Activity is inhibited by binding to OTUB1, which prevents 'Lys-63'-linked polyubiquitination (PubMed:20725033, PubMed:22325355, PubMed:22367539). Activity is inhibited by GPS2, leading to prevent 'Lys-63'-linked polyubiquitination (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterodimer with UBE2V2 (PubMed:10089880, PubMed:11473255, PubMed:14562038, PubMed:16307917, PubMed:16307917). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with RNF8 and RNF168 (PubMed:16215985, PubMed:19203578). Interacts with RNF11 (PubMed:18615712). Interacts with the E3 ligases, HLTF and SHPRH; the interactions promote the 'Lys-63'-linked polyubiquitination of PCNA upon genotoxic stress and lead to DNA repair (PubMed:17108083, PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with ARIH2 (via RING-type 2) (PubMed:19340006). Interacts with OTUB1; leading to inhibit E2-conjugating activity (PubMed:20725033, PubMed:22325355, PubMed:22367539). Interacts with GPS2; leading to inhibit E2-conjugating activity (By similarity). Interacts with DDX58 and RNF135; involved in DDX58 ubiquitination and activation (PubMed:28469175).PTM Conjugation to ISG15 impairs formation of the thioester bond with ubiquitin but not interaction with UBE2V2.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt P61088 1 EQUAL 152 EQUAL Reactome DB_ID: 205753 1 UniProt:Q13404 UBE2V1 UBE2V1 UBE2V P/OKcl.19 CROC1 UBE2V1 UEV1 FUNCTION Has no ubiquitin ligase activity on its own. The UBE2V1-UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through Lys-63. This type of poly-ubiquitination activates IKK and does not seem to involve protein degradation by the proteasome. Plays a role in the activation of NF-kappa-B mediated by IL1B, TNF, TRAF6 and TRAF2. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UBE2N, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.SUBUNIT Heterodimer with UBE2N (PubMed:11057907, PubMed:16307917, PubMed:16893187). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with TRAF6 (PubMed:11057907, PubMed:16307917).TISSUE SPECIFICITY Highly expressed in thyroid, pancreas, spinal cord, lymph node, trachea, adrenal gland, bone marrow and pancreas. Detected at low levels in heart, breast, placenta, brain, liver, kidney, stomach and lung.INDUCTION Down-regulated during differentiation of cultured colon adenocarcinoma cells.MISCELLANEOUS In human, PESD1/KUA and UBE2V1/UEV1 are adjacent genes which can produce independent proteins and can also be fused to form a PESD1-UBE2V1 hybrid protein.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt Q13404 2 EQUAL 147 EQUAL Reactome Database ID Release 81 202463 Database 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=202463 Reactome R-HSA-202463 2 Reactome 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-202463.2 Reactome DB_ID: 975131 1 Reactome DB_ID: 450152 4 K63polyUb [cytosol] K63polyUb K63-polyubiquitin Lys-63 polyubiquitin Reactome DB_ID: 202463 1 Reactome DB_ID: 975174 1 K63-linked poly-Ub-IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9. [endosome membrane] K63-linked poly-Ub-IRF7:TRAF6:p-3S,3T-IRAK1:p-S,2T-IRAK4:oligo-MyD88:activated TLR7/8 or 9. Reactome DB_ID: 975154 4 ubiquitinylated lysine (K63polyUb [endosome membrane]) at unknown position ubiquitinylated lysine [MOD:01148] 1 EQUAL 503 EQUAL Reactome DB_ID: 975148 1 Reactome Database ID Release 81 975174 Database 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=975174 Reactome R-HSA-975174 3 Reactome 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-975174.3 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 975131 GO 0004842 GO molecular function Reactome Database ID Release 81 975176 Database 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=975176 Reactome Database ID Release 81 975118 Database 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=975118 Reactome R-HSA-975118 5 Reactome 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-975118.5 18710948 Pubmed 2008 TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1 Ning, S Campos, AD Darnay, BG Bentz, GL Pagano, JS Mol Cell Biol 28:6536-46 Phosphorylation and release of IRF7 upon TLR7/8 or 9 activation Phosphorylation and release of IRF7 upon TLR7/8 or 9 activation IRF7 is phosphorylated on Ser477 and Ser479 residues [Lin R et al 2000] . IRAK1[Uematsu et al 2005] and IKK alpha[Hoshino et al 2006] are thought to mediate the phosphorylation upon TLR7/8/9 activation. Authored: Shamovsky, V, 2010-08-25 Reviewed: Gillespie, ME, 2010-10-29 Edited: Shamovsky, V, 2010-11-15 Reactome DB_ID: 975131 1 Reactome DB_ID: 113592 8 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 8 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 450318 4 O-phospho-L-serine at 477 477 EQUAL O-phospho-L-serine at 479 479 EQUAL 1 EQUAL 503 EQUAL Reactome DB_ID: 975148 1 Reactome Database ID Release 81 975106 Database 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=975106 Reactome R-HSA-975106 3 Reactome 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-975106.3 11073981 Pubmed 2000 Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain MariƩ, I Smith, E Prakash, A Levy, DE Mol Cell Biol 20:8803-14 10893229 Pubmed 2000 Multiple regulatory domains control IRF-7 activity in response to virus infection Lin, R Mamane, Y Hiscott, J J Biol Chem 275:34320-7 16612387 Pubmed 2006 IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9 Hoshino, K Sugiyama, T Matsumoto, M Tanaka, T Saito, M Hemmi, H Ohara, O Akira, Shizuo Kaisho, T Nature 440:949-53 20200270 Pubmed 2010 Critical role of IkappaB Kinase alpha in TLR7/9-induced type I IFN production by conventional dendritic cells Hoshino, K Sasaki, I Sugiyama, T Yano, T Yamazaki, C Yasui, T Kikutani, H Kaisho, T J Immunol 184:3341-5 Dimerization of p-IRF7 Dimerization of p-IRF7 Phosphorylation stimulates the C-terminal autoinhibitory domain of IRF7 to attain a highly extended conformation triggering dimerization through extensive contacts to a second IRF7 subunit. Authored: Garapati, P V, 2010-08-02 Reviewed: Kawai, T, Akira, S, 2010-10-30 Edited: Garapati, P V, 2010-08-02 Reactome DB_ID: 450318 2 O-phospho-L-serine at 477 477 EQUAL O-phospho-L-serine at 479 479 EQUAL 1 EQUAL 503 EQUAL Reactome DB_ID: 450344 1 p-2S-IRF7:p-2S-IRF7 [cytosol] p-2S-IRF7:p-2S-IRF7 Reactome DB_ID: 450318 2 O-phospho-L-serine at 477 477 EQUAL O-phospho-L-serine at 479 479 EQUAL 1 EQUAL 503 EQUAL Reactome Database ID Release 81 450344 Database 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=450344 Reactome R-HSA-450344 1 Reactome 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-450344.1 Reactome Database ID Release 81 933533 Database 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=933533 Reactome R-HSA-933533 1 Reactome 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-933533.1 20043992 Pubmed 2010 Structural insights into interferon regulatory factor activation Chen, W Royer WE, Jr Cell Signal 22:883-7 Translocation of p-IRF7:p-IRF7 to nucleus Translocation of p-IRF7:p-IRF7 to nucleus p-IRF7 dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes. Authored: Garapati, P V, 2010-08-02 Reviewed: Kawai, T, Akira, S, 2010-10-30 Reviewed: Jin, Lei, 2013-05-21 Reviewed: Wu, Jiaxi, 2013-05-21 Edited: Shamovsky, V, 2013-05-17 Reactome DB_ID: 450344 1 Reactome DB_ID: 450306 1 nucleoplasm GO 0005654 2xp-S477,S479-IRF7 [nucleoplasm] 2xp-S477,S479-IRF7 Reactome DB_ID: 450270 2 O-phospho-L-serine at 477 477 EQUAL O-phospho-L-serine at 479 479 EQUAL 1 EQUAL 503 EQUAL Reactome Database ID Release 81 450306 Database 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=450306 Reactome R-HSA-450306 1 Reactome 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-450306.1 Reactome Database ID Release 81 933531 Database 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=933531 Reactome R-HSA-933531 1 Reactome 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-933531.1 Reactome Database ID Release 81 975110 Database 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=975110 Reactome R-HSA-975110 3 Reactome 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-975110.3 11070172 Pubmed 2000 Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction Sato, M Suemori, H Hata, N Asagiri, M Ogasawara, K Nakao, K Nakaya, T Katsuki, M Noguchi, S Tanaka, N Taniguchi, T Immunity 13:539-48 15153500 Pubmed 2004 Toll-like receptor 9 signaling activates NF-kappaB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells Tsujimura, H Tamura, T Kong, HJ Nishiyama, A Ishii, KJ Klinman, DM Ozato, K J Immunol 172:6820-7 16497588 Pubmed 2006 Pathogen recognition and innate immunity Akira, Shizuo Uematsu, S Takeuchi, O Cell 124:783-801 16214811 Pubmed 2005 Regulation of the type I IFN induction: a current view Honda, K Yanai, H Takaoka, A Taniguchi, T Int Immunol 17:1367-78