BioPAX pathway converted from "TICAM1-dependent activation of IRF3/IRF7" in the Reactome database. TICAM1-dependent activation of IRF3/IRF7 TICAM1-dependent activation of IRF3/IRF7 TLR3-mediated TICAM1-dependent activation of IRF3/IRF7 TLR3-mediated TRIF-dependent activation of IRF3/IRF7 Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon Cell stimulation with viral ds RNA leads to the activation of two IKK-related serine/threonine kinases, TBK1 and IKK-i which directly phosphorylate IRF3 and IRF7 promoting their dimerization and translocation into the nucleus. Although both kinases show structural and functional similarities, it seems that TBK1 and IKK-i differ in their regulation of downstream signaling events of TLR3.<p>IRF3 activation and IFN-b production by poly(I:C) are decreased in TBK1-deficient mouse fibroblasts, whereas normal activation was observed in the IKK-i-deficient fibroblasts. However, in double-deficient mouse fibroblasts, the activation of IRF3 is completely abolished, suggesting a partially redundant functions of TBK1 and IKK-i (Hemmi et al. 2004).<p>TLR3 recruits and activates PI3 kinase (PI3K), which activates the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3 [Sarkar SN et al 2004]. When PI3K is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene. Authored: Shamovsky, V, 2010-06-01 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2010-11-16 TRAF3 binds to TRIF:activated TLR3 complex TRAF3 binds to TRIF:activated TLR3 complex Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is a ubiquitin ligase recruited to both MYD88- and TRIF-assembled signalling complexes [Hacker H et al 2006]. However, TRAF3 controls the production of interferon and proinflammatory cytokines in different ways [Tseng PH et al 2010]. Positive or negative type of regulation is dictated by TRAF3 subcellular distribution and its mode of ubiquitination. Thus, TRIF-mediated signaling initiated on endosomes triggers TRAF3 self-ubiquitination through noncanonical (K63-linked) polyubiquitination, which is essential for activation of IRF3/7 and the interferon response. In contrast, during MyD88-dependent signaling initiated from plasma membrane TRAF3 functions as a negative regulator of inflammatory cytokines and mitogen-activated protein kinases (MAPKs), unless it undergoes degradative (K48-linked) polyubiquitination mediated by TRAF6 and a pair of the ubiquitin ligases cIAP1 and cIAP2. The degradation of TRAF3 is essential for MAPK activation via TAK1 and MEKK1 [Tseng PH et al 2010]. Authored: Shamovsky, V, 2012-04-26 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2012-05-25 Reactome DB_ID: 914241 2 cytosol GO 0005829 UniProt:Q13114 TRAF3 TRAF3 CAP1 TRAF3 CRAF1 FUNCTION Regulates pathways leading to the activation of NF-kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'-linked ubiquitination of target proteins. Inhibits activation of NF-kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa-B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14.SUBUNIT Homotrimer. Heterotrimer with TRAF2 and TRAF5. Interacts with LTBR/TNFRSF3, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF13C TNFRSF17/BCMA, TLR4 and EDAR. Interacts with MAP3K5, MAP3K14, TRAIP/TRIP, TDP2/TTRAP, TANK/ITRAF and TRAF3IP1. Interaction with TNFRSF5/CD40 is modulated by TANK/ITRAF, which competes for the same binding site. Interacts with TICAM1. Interacts with TRAFD1. Interacts with OTUB1, OTUB2 and OTUD5. Interacts with RNF216, OPTN and TBK1. Identified in a complex with TRAF2, MAP3K14 and BIRC3. Interacts with BIRC2 and BIRC3. Upon exposure to bacterial lipopolysaccharide (LPS), recruited to a transient complex containing TLR4, TRAF3, TRAF6, IKBKG, MAP3K7, MYD88, TICAM1, BIRC2, BIRC3 and UBE2N (By similarity). Interacts with Epstein-Barr virus protein LMP1. Interacts (via RING-type zinc finger domain) with SRC. Interacts with CARD14. Interacts (via MATH domain) with PTPN22; the interaction promotes TRAF3 polyubiquitination (PubMed:23871208). Interacts with MAVS (PubMed:19893624, PubMed:27980081). Directly interacts with DDX3X; this interaction stimulates TRAF3 'Lys-63' ubiquitination (PubMed:27980081). Interacts with IRF3 (PubMed:27980081). Interacts with IKBKE in the course of Sendai virus infection (PubMed:27980081). Interacts with TRIM35 (PubMed:32562145). Interacts with GAPDH; promoting TRAF3 ubiquitination (PubMed:27387501).DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.DOMAIN The Ring-type zinc finger domain is required for its function in down-regulation of NFKB2 proteolytic processing.PTM Undergoes 'Lys-48'-linked polyubiquitination, leading to its proteasomal degradation in response to signaling by TNFSF13B, TLR4 or through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated by OTUD7B, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during early stages of virus infection, and 'Lys-48'-linked ubiquitination during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked ubiquitination in response to TLR3 and TLR4 signaling. 'Lys-63'-linked ubiquitination can be mediated by TRIM35. Deubiquitinated by OTUB1, OTUB2 and OTUD5. Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to terminate the pattern-recognition receptors/PRRs pathways (By similarity).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt Q13114 Chain Coordinates 1 EQUAL 568 EQUAL Reactome DB_ID: 168907 1 endosome membrane GO 0010008 viral dsRNA:TLR3:TICAM1 [endosome membrane] viral dsRNA:TLR3:TICAM1 viral dsRNA:TLR3:TRIF Reactome DB_ID: 450316 2 UniProt:Q8IUC6 TICAM1 TICAM1 PRVTIRB TICAM1 TRIF FUNCTION Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis (PubMed:12471095, PubMed:12539043, PubMed:14739303, PubMed:28747347). Ligand binding to these receptors results in TRIF recruitment through its TIR domain (PubMed:12471095, PubMed:12539043, PubMed:14739303). Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively (PubMed:12471095, PubMed:12539043, PubMed:14739303). Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens (PubMed:25636800). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of proinflammatory cytokines (By similarity).SUBUNIT Homodimer (PubMed:12539043). Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without poly(I:C) RNA ligand stimulation. Interacts (via TIR domain) with DDX21 (via C-terminus). Interacts (via TIR domain) with DHX36 (via C-terminus) (By similarity). Interacts with AZI2 and IRF7 (PubMed:12471095, PubMed:15611223). Interacts with TICAM2 in TLR4 recruitment (PubMed:12721283, PubMed:25736436). Interaction with PIAS4 inhibits the TICAM1-induced NF-kappa-B, IRF and IFNB1 activation (PubMed:15251447). Interacts with IKBKB and IKBKE. Interaction with SARM1 blocks TICAM1-dependent transcription factor activation (PubMed:16964262). Interacts with TRAF3 (By similarity). Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (PubMed:12471095, PubMed:14739303, PubMed:25636800, PubMed:27302953). Interacts with TBK1, TRAF6 and RIPK1 and these interactions are enhanced in the presence of WDFY1 (PubMed:14982987, PubMed:25736436). Interacts with TRAFD1 (By similarity). Interacts with UBQLN1 (via UBA domain) (PubMed:21695056). Interacts with TLR4 in response to LPS in a WDFY1-dependent manner (By similarity). Interacts with WDFY1 in response to poly(I:C) (By similarity). Interacts (via the TIR domain) with TLR3 in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with TRIM56 (PubMed:22948160). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of proinflammatory cytokines (By similarity). Interacts (via the TIR domain) with TLR5 (PubMed:20855887). Interacts with TRIM8 (PubMed:28747347).SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) NS3/4A protease; this interaction leads to TICAM1 cleavage, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state.SUBUNIT (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TICAM1/TRIF and subsequent suppression of host innate immunity.SUBUNIT (Microbial infection) Interacts (via C-terminus) with coxsackievirus B3 (CVB3) protease 3C.TISSUE SPECIFICITY Ubiquitously expressed but with higher levels in liver.DOMAIN The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of TICAM1 recruits IRF3 (PubMed:25636800). IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines (PubMed:25636800).DOMAIN The N-terminal region is essential for activation of the IFNB promoter activity.DOMAIN The N-terminal domain (TRIF-NTD) is globular and consists of two alpha-helical subdomains connected by a 14-residue linker. It shares structural similarity with IFIT family members N-terminal regions.PTM Phosphorylated by TBK1 (PubMed:14530355, PubMed:25636800). Following activation, phosphorylated by TBK1 at Ser-210 in the pLxIS motif (PubMed:25636800). The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines (PubMed:25636800, PubMed:27302953).PTM Polyubiquitinated at Lys-229 by TRIM38 with 'Lys-48'-linked chains, leading to proteasomal degradation (PubMed:23056470). Polyubiquitinated with 'Lys-6'- and 'Lys-33'-linked chains in a TRIM8-dependent manner; ubiquitination disrupts the interaction with TBK1 and subsequent interferon production (PubMed:28747347).PTM (Microbial infection) Cleaved and degraded by hepatitis A virus (HAV) protein 3CD allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by CVB3 protease 3C allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by protease 3C of human enterovirus D68 (EV68) allowing the virus to disrupt host TLR3 signaling.PTM (Microbial infection) Cleaved by HCV protease NS3/4A, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state. UniProt Q8IUC6 1 EQUAL 712 EQUAL Reactome DB_ID: 167985 1 viral dsRNA :TLR3 [endosome membrane] viral dsRNA :TLR3 Reactome DB_ID: 2000341 2 UniProt:O15455 TLR3 TLR3 TLR3 FUNCTION Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.SUBUNIT Monomer and homodimer; dimerization is triggered by ligand-binding, the signaling unit is composed of one ds-RNA of around 40 bp and two TLR3 molecules, and lateral clustering of signaling units along the length of the ds-RNA ligand is required for TLR3 signal transduction. Interacts (via transmembrane domain) with UNC93B1; the interaction is required for transport from the ER to the endosomes (PubMed:33432245). Interacts with SRC; upon binding of double-stranded RNA. Interacts with TICAM1 (via the TIR domain) in response to poly(I:C) and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). The tyrosine-phosphorylated form (via TIR domain) interacts with WDFY1 (via WD repeat 2) in response to poly(I:C) (PubMed:25736436).TISSUE SPECIFICITY Expressed at high level in placenta and pancreas. Also detected in CD11c+ immature dendritic cells. Only expressed in dendritic cells and not in other leukocytes, including monocyte precursors. TLR3 is the TLR that is expressed most strongly in the brain, especially in astrocytes, glia, and neurons.DOMAIN ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18.PTM Heavily N-glycosylated, except on that part of the surface of the ectodomain that is involved in ligand binding.PTM TLR3 signaling requires a proteolytic cleavage mediated by cathepsins CTSB and CTSH, the cleavage occurs between amino acids 252 and 346. The cleaved form of TLR3 is the predominant form found in endosomes.POLYMORPHISM The Phe-412 allele (dbSNP:rs3775291) occurs with a frequency of 30% in populations with European and Asian ancestry, and confers some natural resistance to HIV-1 infection.SIMILARITY Belongs to the Toll-like receptor family. UniProt O15455 24 EQUAL 904 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9038432 1 endosome lumen GO 0031904 TLR3 ligand [endosome lumen] 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 167985 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=167985 Reactome R-HSA-167985 4 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-167985.4 Reactome Database ID Release 81 168907 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=168907 Reactome R-HSA-168907 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-168907.3 Reactome DB_ID: 9013984 1 TRAF3:TICAM1:viral dsRNA:TLR3 [endosome membrane] TRAF3:TICAM1:viral dsRNA:TLR3 TRAF3:TRIF:activated TLR3 Reactome DB_ID: 914241 2 1 EQUAL 568 EQUAL Reactome DB_ID: 168907 1 Reactome Database ID Release 81 9013984 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=9013984 Reactome R-HSA-9013984 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-9013984.2 Reactome Database ID Release 81 9013992 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=9013992 Reactome R-HSA-9013992 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-9013992.2 16306936 Pubmed 2006 Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response Oganesyan, G Saha, SK Guo, B He, JQ Shahangian, A Zarnegar, B Perry, A Cheng, G Nature 439:208-11 16306937 Pubmed 2006 Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 Häcker, H Redecke, V Blagoev, B Kratchmarova, I Hsu, LC Wang, GG Kamps, MP Raz, E Wagner, H Häcker, G Mann, M Karin, M Nature 439:204-7 19898473 Pubmed 2010 Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines Tseng, PH Matsuzawa, A Zhang, W Mino, T Vignali, DA Karin, M Nat Immunol 11:70-5 6.3.2.19 Auto-ubiquitination of TRAF3 within activated TLR3 complex Auto-ubiquitination of TRAF3 within activated TLR3 complex TRIF(TICAM1) signaling activates TRAF3 self-mediated polyubiquitination trough Lys-63 of ubiquitin. The ubiquitinated TRAF3 in turn activates the interferon response (Tseng PH et al. 2010). Authored: Shamovsky, V, 2012-04-26 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2012-05-25 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBB(153-228) [cytosol] RPS27A(1-76) [cytosol] UBB(1-76) [cytosol] UBC(457-532) [cytosol] UBC(153-228) [cytosol] UBC(77-152) [cytosol] UBC(305-380) [cytosol] UBC(1-76) [cytosol] UBC(229-304) [cytosol] UBB(77-152) [cytosol] UBA52(1-76) [cytosol] UBC(533-608) [cytosol] UBC(381-456) [cytosol] UBC(609-684) [cytosol] UniProt P0CG47 UniProt P62979 UniProt P0CG48 UniProt P62987 Reactome DB_ID: 9013984 1 Reactome DB_ID: 9013989 1 K63polyUb-TRAF3:TICAM1:activated TLR3 [endosome membrane] K63polyUb-TRAF3:TICAM1:activated TLR3 K63polyUb-TRAF3:TRIF:activated TLR3 Reactome DB_ID: 936402 2 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at unknown position ubiquitinylated lysine [MOD:01148] 1 EQUAL 568 EQUAL Reactome DB_ID: 168907 1 Reactome Database ID Release 81 9013989 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=9013989 Reactome R-HSA-9013989 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-9013989.2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9013984 GO 0004842 GO molecular function Reactome Database ID Release 81 9014563 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=9014563 Reactome Database ID Release 81 9013974 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=9013974 Reactome R-HSA-9013974 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-9013974.2 TANK binds K63-poly-Ub-TRAF3:TICAM1:activated TLR3 TANK binds K63-poly-Ub-TRAF3:TICAM1:activated TLR3 TRAF family member-associated NFkB activator (TANK or ITRAF) is a TRAF-binding protein that has been implicated in RLR, TNFR and IL-1R/TLR signaling pathways in mammals (Rothe M et a.l 1996; Pomerantz JL and Baltimore D 1999; Li C et al. 2002; Guo B and Cheng G 2007; Konno H 2009). TANK was shown to interact with TBK1, IKK epsilon, IPS-1, TRIF (TICAM1), IRF3 and is thought to be a part of the TRAF3-containing complex (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007). Upon microbe stimulation TANK is believed to induce IRF-dependent type I IFN production in mammalian cells by linking kinase TBK1 or IKK epsilon with upstream mediators TRAF3/6 (Guo B and Cheng G 2007; Gatot JC et al. 2007). In addition, TANK is thought to act synergistically with IKK epsilon or TBK1 to link them to IKK complex via interaction with NEMO (IKK gamma), where TBK1/IKK epsilon may modulate NFkB activation (Chariot A et al. 2002). TANK influence on NFkB activation was found to occur via either positive or negative regulation (Guo B and Cheng G 2007, Konno H et al. 2009; Pomerantz JL and Baltimore D 1999; Kawagoe T et al. 2009).<p> Two other adaptor proteins NAK-associated protein 1 (NAP1) and SINTBAD (not shown here) have been implicated in TBK1/IKKepsilon-mediated activation of IRF3 (Sasai M et al. 2005; Ryzhakov G and Randow F 2007). Structural and functional studies showed that TANK, NAP1 and SINTBAD share a common region which mediates association with the coiled-coil 2 in TBK1 (Ryzhakov G and Randow F 2007; Goncalves A et al. 2011; Larabi A et al. 2013; Tu D et al. 2013). TANK, NAP1 and SINTBAD were found to compete for TBK1 binding (Ryzhakov G and Randow F 2007; Goncalves A et al. 2011), TBK1 is thought to form alternative complexes with each adaptor TANK, NAP1 or SINTBAD, rather than a single large multiprotein complex containing all three adaptors (Goncalves A et al. 2011; Larabi A et al. 2013). Authored: Shamovsky, V, 2014-05-16 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2014-05-16 Reactome DB_ID: 933407 2 UniProt:Q92844 TANK TANK ITRAF TRAF2 TANK FUNCTION Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Acts as a regulator of TRAF function by maintaining them in a latent state. Blocks TRAF2 binding to LMP1 and inhibits LMP1-mediated NF-kappa-B activation. Negatively regulates NF-kappaB signaling and cell survival upon DNA damage (PubMed:25861989). Plays a role as an adapter to assemble ZC3H12A, USP10 in a deubiquitination complex which plays a negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Promotes UBP10-induced deubiquitination of TRAF6 in response to DNA damage (PubMed:25861989). May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2.SUBUNIT Homodimer. Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta-mediated NF-kappaB activation by promoting IKBKG or TRAF6 deubiquitination (PubMed:25861989). Interacts with IKBKG; this interaction increases in response to DNA damage (PubMed:25861989). Interacts with TRAF6; this interaction increases in response to DNA damage and recruits USP10 to the ubiquitinated TRAF6 (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 (PubMed:25861989). Interacts with TBK1 (PubMed:10581243, PubMed:21931631, PubMed:29251827). Interacts with IKBKE (PubMed:17568778). Interacts also with TRAF1, TRAF2, and TRAF3 by binding to their TRAF-C domains; the interaction with TRAF2 is disrupted by the phosphorylation of TANK by IKBKE (PubMed:10759890, PubMed:12005438). Interacts more strongly with TRAF1 and TRAF2 than TRAF3 (PubMed:10759890, PubMed:12005438). Interacts with IKBKG; the interaction is enhanced by IKBKE and TBK1 (PubMed:12133833). Part of a ternary complex consisting of TANK, IKBKB and IKBKG (PubMed:12133833).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C6 (PubMed:21931555).SUBUNIT (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TANK and subsequent suppression of host innate immunity.TISSUE SPECIFICITY Ubiquitous.PTM Phosphorylated by IKBKE.PTM (Microbial infection) Cleaved by encephalomyocarditis virus (EMCV) protease 3C (PubMed:26363073). This cleavage allows the virus to disrupt the TANK-TBK1-IKKepsilon-IRF3 complex, thereby inhibiting the induction of the IFN-beta signal pathway (PubMed:28487378).PTM (Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to suppress interferon type-I through both RIG-I and Toll-like receptor-dependent pathways. UniProt Q92844 1 EQUAL 425 EQUAL Reactome DB_ID: 9013989 1 Reactome DB_ID: 9013980 1 TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3 [endosome membrane] TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3 TANK:K63-poly-Ub-TRAF3:TRIF:activated TLR3 TANK:K63-poly-Ub-TRAF3:TICAM1:activated TLR3 Reactome DB_ID: 933407 2 1 EQUAL 425 EQUAL Reactome DB_ID: 9013989 1 Reactome Database ID Release 81 9013980 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=9013980 Reactome R-HSA-9013980 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-9013980.2 Reactome Database ID Release 81 9013985 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=9013985 Reactome R-HSA-9013985 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-9013985.2 19479062 Pubmed 2009 TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA Konno, H Yamamoto, T Yamazaki, K Gohda, J Akiyama, T Semba, K Goto, H Kato, A Yujiri, T Imai, T Kawaguchi, Y Su, B Takeuchi, O Akira, Shizuo Tsunetsugu-Yokota, Y Inoue, J PLoS One 4:e5674 12133833 Pubmed 2002 Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases Chariot, A Leonardi, A Muller, J Bonif, M Brown, K Siebenlist, U J Biol Chem 277:37029-36 17327220 Pubmed 2007 Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK Guo, B Cheng, G J Biol Chem 282:11817-26 19668221 Pubmed 2009 TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis Kawagoe, T Takeuchi, O Takabatake, Y Kato, H Isaka, Y Tsujimura, T Akira, Shizuo Nat Immunol 10:965-72 21931631 Pubmed 2011 Functional dissection of the TBK1 molecular network Goncalves, Adriana Bürckstümmer, Tilmann Dixit, Evelyn Scheicher, Ruth Górna, Maria W Karayel, Evren Sugar, Cristina Stukalov, Alexey Berg, Tiina Kralovics, Robert Planyavsky, Melanie Bennett, Keiryn L Colinge, Jacques Superti-Furga, Giulio PLoS ONE 6:e23971 15611223 Pubmed 2005 Cutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation Sasai, Miwa Oshiumi, H Matsumoto, M Inoue, N Fujita, Fumitaka Nakanishi, Makoto Seya, T J. Immunol. 174:27-30 17823124 Pubmed 2007 Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF Gatot, Jean-Stéphane Gioia, Romain Chau, Tieu-Lan Patrascu, Félicia Warnier, Michael Close, Pierre Chapelle, Jean-Paul Muraille, Eric Brown, Keith Siebenlist, Ulrich Piette, Jacques Dejardin, Emmanuel Chariot, Alain J. Biol. Chem. 282:31131-46 10581243 Pubmed 1999 NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase Pomerantz, JL Baltimore, D EMBO J 18:6694-704 23453972 Pubmed 2013 Structure and ubiquitination-dependent activation of TANK-binding kinase 1 Tu, Daqi Zhu, Zehua Zhou, Alicia Y Yun, Cai-hong Lee, Kyung-Eun Toms, Angela V Li, Y Dunn, Gavin P Chan, Edmond Thai, Tran Yang, Shenghong Ficarro, Scott B Marto, Jarrod A Jeon, H Hahn, WC Barbie, David A Eck, Michael J Cell Rep 3:747-58 12005438 Pubmed 2002 Downstream regulator TANK binds to the CD40 recognition site on TRAF3 Li, Chenglong Ni, Chao-Zhou Havert, Marnie L Cabezas, Edelmira He, Jeannie Kaiser, Donald Reed, John C Satterthwait, Arnold C Cheng, Genhong Ely, Kathryn R Structure 10:403-11 17568778 Pubmed 2007 SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK Ryzhakov, Grigory Randow, Felix EMBO J. 26:3180-90 8710854 Pubmed 1996 I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction Rothe, M Xiong, J Shu, H B Williamson, K Goddard, A Goeddel, DV Proc. Natl. Acad. Sci. U.S.A. 93:8241-6 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 23453971 Pubmed 2013 Crystal structure and mechanism of activation of TANK-binding kinase 1 Larabi, Amede Devos, Juliette M Ng, Sze-Ling Nanao, Max H Round, Adam Maniatis, Tom Panne, Daniel Cell Rep 3:734-46 TANK is ubiquitinated within TANK:K63polyUb-TRAF3:TICAM1:TLR3:viral dsRNA TANK is ubiquitinated within TANK:K63polyUb-TRAF3:TICAM1:TLR3:viral dsRNA TANK is ubiquitinated within TANK:K63polyUb-TRAF3:TICAM1:activated TLR3 Upon stimulation by pathogen-associated inflammatory signals TANK associates with TRAF3 which may result in K63-linked ubiquitination of TANK (Gatot JC et al. 2007). How the ubiquitination of TANK contributes to the activation of TBK1 and/or IKKepsilon remains unclear. Authored: Shamovsky, V, 2014-05-16 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2014-05-16 Reactome DB_ID: 9013980 1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome DB_ID: 9013976 1 K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNA [endosome membrane] K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNA K63pUb-TANK:K63pUb-TRAF3:TRIF:activated TLR3 Reactome DB_ID: 5362480 2 ubiquitinylated lysine (K63polyUb [cytosol]) at unknown position 1 EQUAL 425 EQUAL Reactome DB_ID: 9013989 1 Reactome Database ID Release 81 9013976 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=9013976 Reactome R-HSA-9013976 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-9013976.2 Reactome Database ID Release 81 9013990 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=9013990 Reactome R-HSA-9013990 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-9013990.2 Recruitment of TBK1/IKK epsilon to K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR3 followed by their phosphorylation Recruitment of TBK1/IKK epsilon to K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR3 followed by their phosphorylation Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and inhibitor of kappaB kinase epsilon (IKKi) induce type I interferon expression and modulate nuclear factor kappa B (NFkB) signaling (Fitzgerald KA et al. 2003; Hemmi H et al. 2004). The structural studies of TBK1 revealed a dimeric assembly which is mediated by several interfaces involving kinase domain (KD), a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al. 2013; Tu D et al. 2013). ULD of TBK1 and IKKi was involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al 2007; Tu D et al. 2013). An intact TBK1 dimer was a subject to K63-linked polyubiquitination on lysines 30 and 401 (Tu D et al. 2013). Activation of TBK1 rearranged the KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al. 2013). The ubiquitination sites and dimer contacts are conserved in the close homolog IKKi (Tu D et al. 2013). The activation of TBK1 and IKKi may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al. 2009). Other studies demonstrated an essential role of TRAF3 in the activation of TBK1 (Hacker et al 2006). TBK1 and IKKi were found to interact with scaffold proteins TANK (TRAF family member associated NFkB activator), NAP1 (NAK-associated protein 1), SINTBAD (similar to NAP1 TBK1 adaptor) which connect TBK1/IKKi to pathogen-activated signaling cascades (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007; Ryzhakov G and Randow F 2007; Goncalves A et al. 2011). Authored: Shamovsky, V, 2010-06-01 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2014-05-16 Reactome DB_ID: 9013976 1 Reactome DB_ID: 113592 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Converted from EntitySet in Reactome Reactome DB_ID: 450329 2 TBK1, IKBKE [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity IKBKE [cytosol] TBK1 [cytosol] UniProt Q14164 UniProt Q9UHD2 Reactome DB_ID: 29370 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 9013982 1 activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKi [endosome membrane] activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKi Reactome DB_ID: 9013976 1 Converted from EntitySet in Reactome Reactome DB_ID: 450251 2 activated TBK1/IKK epsilon [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-S172-TBK1 [cytosol] p-S172-IKBKE [cytosol] Reactome Database ID Release 81 9013982 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=9013982 Reactome R-HSA-9013982 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-9013982.2 Reactome Database ID Release 81 9013986 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=9013986 Reactome R-HSA-9013986 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-9013986.2 15210742 Pubmed 2004 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and Hemmi, H Takeuchi, O Sato, S Yamamoto, M Kaisho, T Sanjo, H Kawai, T Hoshino, K Takeda, K J Exp Med 199:1641-50 17599067 Pubmed 2007 Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes Ikeda, F Hecker, CM Rozenknop, A Nordmeier, RD Rogov, V Hofmann, K Akira, Shizuo Dötsch, V Dikic, I EMBO J 26:3451-62 12692549 Pubmed 2003 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway Fitzgerald, Katherine A McWhirter, SM Faia, KL Rowe, DC Latz, E Golenbock, DT Coyle, AJ Liao, SM Maniatis, T Nat Immunol 4:491-6 19307177 Pubmed 2009 Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation Clark, K Plater, L Peggie, M Cohen, P J Biol Chem 284:14136-46 IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3 IRF3/IRF7 recruitment to p-TBK1/p-IKK epsilon bound to the activated TLR3 Two members of the interferon regulatory factor (IRF) family IRF3 and IRF7 are the major modulators of IFN gene expression (Hemmi H et al. 2004). Activation of IRF3 and IRF7, which is mediated by TBK1/IKK protein kinases, promotes IFN gene expression and the production of IFN developing an effective antiviral immune response (Hemmi H et al. 2004).<p>Irf-3 deficient mice were found to be more vulnerable to virus infection. Mouse cells defective in IRF3 and IRF7 expression totally fail to induce IFN genes in response to viral infection. It was shown on mice and mouse cells that both IRF3 and IRF7 have non redundant and distinct roles (Sato M et al. 2000). IRF3 is expressed at a basal level in normally growing cells and is a major factor in the early induction phase of IFN-alpha/beta production, while the IRF7 gene expression is induced upon IFNs stimulation and IRF7 is involved in the late induction phase.<br> SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proinflammatory cytokines and type I interferon in LPS or poly(I-C)-stimulated mouse peritoneal macrophages. SHP-2 overexpression also inhibited TRIF-induced IFN-luciferase reporter gene expression in human embryonic kidney HEK293 cells. Experiments with truncated SHP-2 or truncated TBK1 mutants revealed that C-terminal domain of SHP-2 associates with N-terminal domain of TBK1 when coexpressed in HEK293 cells. Furthermore, SHP-2 is thought to prevent TBK1-mediated downstream substrate phosphorylation in tyrosine phosphatase activity independent manner by binding to kinase domain of TBK1 (An H et al. 2006). Authored: de Bono, B, 2005-08-16 10:54:15 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2014-05-16 Reactome DB_ID: 9013982 1 Converted from EntitySet in Reactome Reactome DB_ID: 450317 2 IRF3,IRF7 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity IRF3 [cytosol] IRF7 [cytosol] UniProt Q14653 UniProt Q92985 Reactome DB_ID: 9013981 1 activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7 [endosome membrane] activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7 Reactome DB_ID: 9013982 1 Converted from EntitySet in Reactome Reactome DB_ID: 450317 2 Reactome Database ID Release 81 9013981 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=9013981 Reactome R-HSA-9013981 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-9013981.2 Reactome Database ID Release 81 9013979 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=9013979 Reactome R-HSA-9013979 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-9013979.2 14703513 Pubmed 2004 Identification of Ser-386 of interferon regulatory factor 3 as critical Mori, M Yoneyama, M Ito, T Takahashi, K Inagaki, F Fujita, Toshiro J Biol Chem 279:9698-702 9566918 Pubmed 1998 Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation Lin, R Heylbroeck, C Pitha-Rowe, Paula M Hiscott, J Mol Cell Biol 18:2986-96 17157040 Pubmed 2006 SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production An, Huazhang Zhao, W Hou, Jin Zhang, Y Xie, Yun Zheng, Yuejuan Xu, Hongmei Qian, Cheng Zhou, Jun Yu, Yizhi Liu, Shuxun Feng, G Cao, X Immunity 25:919-28 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 2.7.11.1 Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex Phosphorylation of IRF-3/IRF7 and their release from the activated TLR3 complex Human IRF3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi. It requires Ser386 and/or Ser385 (site 1) and a cluster of serine/threonine residues between Ser396 and Ser405 (site 2) (Panne et al. 2007). Phosphorylated residues at site 2 alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1. Phosphorylation at site 1 is required for IRF3 dimerization.<p>IRF3 and IRF7 transcription factors possess distinct structural characteristics; IRF7 is phosphorylated on Ser477 and Ser479 residues (Lin R et al. 2000). TRAF6 mediated ubiquitination of IRF7 is also required and essential for IRF7 phosphorylation and activation. The K-63 linked ubiquitination occurs on the last three C-terminal lysine sites (positions 444, 446, and 452) of human IRF7 independently of its C-terminal functional phosphorylation sites.(Ning et al. 2008). Authored: de Bono, B, 2005-08-16 10:54:15 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Reviewed: Masci, Anna Maria, 2014-05-16 Edited: Shamovsky, V, 2014-05-16 Reactome DB_ID: 9013981 1 Reactome DB_ID: 113592 6 Converted from EntitySet in Reactome Reactome DB_ID: 450240 2 p-4S,T404-IRF3,p-S477,S479-IRF7 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-4S,T404-IRF3 [cytosol] p-S477,S479-IRF7 [cytosol] Reactome DB_ID: 29370 6 Reactome DB_ID: 9013982 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9013981 GO 0004674 GO molecular function Reactome Database ID Release 81 9013988 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=9013988 Reactome Database ID Release 81 9013978 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=9013978 Reactome R-HSA-9013978 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-9013978.2 17526488 Pubmed 2007 Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch Panne, D McWhirter, SM Maniatis, T Harrison, SC J Biol Chem 282:22816-22 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 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 Dimerization of phosphorylated IRF3/IRF7 Dimerization of phosphorylated IRF3/IRF7 Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300. Authored: Shamovsky, V, 2009-12-16 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2011-08-12 Converted from EntitySet in Reactome Reactome DB_ID: 450240 2 Converted from EntitySet in Reactome Reactome DB_ID: 450256 1 phosphorylated IRF3 and/or IRF7 dimer [cytosol] 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 168933 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=168933 Reactome R-HSA-168933 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-168933.1 14555995 Pubmed 2003 X-ray crystal structure of IRF-3 and its functional implications Takahasi, K Suzuki, NN Horiuchi, M Mori, M Suhara, W Okabe, Y Fukuhara, Y Terasawa, H Akira, Shizuo Fujita, T Inagaki, F Nat Struct Biol 10:922-7 Dimerized phospho-IRF3/IRF7 is transported to the nucleus Dimerized phospho-IRF3/IRF7 is transported to the nucleus IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm. Authored: Shamovsky, V, 2009-12-16 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Reviewed: Fitzgerald, Katherine A, 2012-11-13 Edited: Shamovsky, V, 2011-08-12 Converted from EntitySet in Reactome Reactome DB_ID: 450256 1 Converted from EntitySet in Reactome Reactome DB_ID: 450349 1 nucleoplasm GO 0005654 phosphorylated IRF3 and/or IRF7 dimer [nucleoplasm] 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 177671 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=177671 Reactome R-HSA-177671 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-177671.2 Reactome Database ID Release 81 9013973 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=9013973 Reactome R-HSA-9013973 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-9013973.2 17332413 Pubmed 2007 Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity Tenoever, BR Ng, SL Chua, MA McWhirter, SM Garcia-Sastre, A Maniatis, T Science 315:1274-8 15502848 Pubmed 2004 Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling Sarkar, SN Peters, KL Elco, CP Sakamoto, S Pal, S Sen, GC Nat Struct Mol Biol 11:1060-7 14679297 Pubmed 2004 IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts McWhirter, SM Fitzgerald, Katherine A Rosains, J Rowe, DC Golenbock, DT Maniatis, T Proc Natl Acad Sci U S A 101:233-8 GO 0035666 GO biological process