BioPAX pathway converted from "Auto-ubiquitination of TRAF3 within activated TLR3 complex" in the Reactome database. LEFT-TO-RIGHT 6.3.2.19 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 Ub ubiquitin Reactome DB_ID: 113595 RPS27A RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939205 cytosol GENE ONTOLOGY GO:0005829 UniProt:P62979 RPS27A RPS27A UBA80 UBCEP1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. Homo sapiens NCBI Taxonomy 9606 UniProt P62979 1 EQUAL 76 EQUAL Reactome Database ID Release 82 939205 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=939205 Reactome R-HSA-939205 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-939205.1 Reactome http://www.reactome.org UBA52 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939203 UniProt:P62987 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit (PubMed:23169626, PubMed:23636399, PubMed:32669547). Interacts with UBQLN1 (via UBA domain) (PubMed:15147878).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62987 1 EQUAL 76 EQUAL Reactome Database ID Release 82 939203 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=939203 Reactome R-HSA-939203 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-939203.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939214 UniProt:P0CG47 UBB UBB SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG47 1 EQUAL 76 EQUAL Reactome Database ID Release 82 939214 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=939214 Reactome R-HSA-939214 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-939214.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939213 77 EQUAL 152 EQUAL Reactome Database ID Release 82 939213 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=939213 Reactome R-HSA-939213 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-939213.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939230 153 EQUAL 228 EQUAL Reactome Database ID Release 82 939230 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=939230 Reactome R-HSA-939230 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-939230.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939188 UniProt:P0CG48 UBC UBC MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG48 1 EQUAL 76 EQUAL Reactome Database ID Release 82 939188 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=939188 Reactome R-HSA-939188 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-939188.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939164 77 EQUAL 152 EQUAL Reactome Database ID Release 82 939164 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=939164 Reactome R-HSA-939164 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-939164.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939258 153 EQUAL 228 EQUAL Reactome Database ID Release 82 939258 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=939258 Reactome R-HSA-939258 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-939258.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939192 229 EQUAL 304 EQUAL Reactome Database ID Release 82 939192 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=939192 Reactome R-HSA-939192 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-939192.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939232 305 EQUAL 380 EQUAL Reactome Database ID Release 82 939232 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=939232 Reactome R-HSA-939232 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-939232.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939191 381 EQUAL 456 EQUAL Reactome Database ID Release 82 939191 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=939191 Reactome R-HSA-939191 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-939191.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939184 457 EQUAL 532 EQUAL Reactome Database ID Release 82 939184 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=939184 Reactome R-HSA-939184 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-939184.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939239 533 EQUAL 608 EQUAL Reactome Database ID Release 82 939239 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=939239 Reactome R-HSA-939239 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-939239.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939165 609 EQUAL 684 EQUAL Reactome Database ID Release 82 939165 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=939165 Reactome R-HSA-939165 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-939165.1 Reactome Database ID Release 82 113595 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=113595 Reactome R-HSA-113595 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-113595.1 TRAF3:TRIF:activated TLR3 TRAF3:TICAM1:viral dsRNA:TLR3 Reactome DB_ID: 9013984 endosome membrane GENE ONTOLOGY GO:0010008 TRAF3 TNF receptor-associated factor 3 TRAF3_HUMAN Reactome DB_ID: 914241 UniProt:Q13114 TRAF3 TRAF3 CAP-1 CRAF1 TRAFAMN FUNCTION Cytoplasmic E3 ubiquitin ligase that regulates various signaling pathways, such as the NF-kappa-B, mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) pathways, and thus controls a lot of biological processes in both immune and non-immune cell types (PubMed:33148796, PubMed:33608556). In TLR and RLR signaling pathways, acts as an E3 ubiquitin ligase promoting the synthesis of 'Lys-63'-linked polyubiquitin chains on several substrates such as ASC that lead to the activation of the type I interferon response or the inflammasome (PubMed:25847972, PubMed:27980081). Following the activation of certain TLRs such as TLR4, acts as a negative NF-kappa-B regulator, possibly to avoid unregulated inflammatory response, and its degradation via 'Lys-48'-linked polyubiquitination is required for MAPK activation and production of inflammatory cytokines. Alternatively, when TLR4 orchestrates bacterial expulsion, TRAF3 undergoes 'Lys-33'-linked polyubiquitination and subsequently binds to RALGDS, mobilizing the exocyst complex to rapidly expel intracellular bacteria back for clearance (PubMed:27438768). Acts also as a constitutive negative regulator of the alternative NF-kappa-B pathway, which controls B-cell survival and lymphoid organ development. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. 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 (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). Interacts with PPP3CA and PPP3CB (By similarity). Interacts with ATP1B1; promoting TRAF3 ubiquitination (PubMed:27387501). Interacts with RALGDS (PubMed:27438768).SUBUNIT (Microbial infection) Interacts (via N-terminus) with New York hantavirus glycoprotein N (via C-terminus); this interaction inhibits the formation of TRAF3-TBK1 complexes.SUBUNIT (Microbial infection) Interacts with Andes hantavirus glycoprotein N (via C-terminus); this interaction inhibits the formation of TRAF3-TBK1 complexes.SUBUNIT (Microbial infection) Interacts with Tula hantavirus glycoprotein N (via C-terminus); this interaction inhibits the formation of TRAF3-TBK1 complexes.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein LMP1.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). Undergoes also 'Lys-29'-linked ubiquitination on Cys-56 and Cys-124 by NEDD4L; leading to increased 'Lys-48'- and 'Lys-63'-linked ubiquitination as well as increased binding to TBK1 (PubMed:33608556). TLR4 signals emanating from bacteria containing vesicles trigger 'Lys-33'-linked polyubiquitination that promotes the assembly of the exocyst complex thereby connecting innate immune signaling to the cellular trafficking apparatus (PubMed:27438768). Deubiquitinated by USP25 during viral infection, leading to TRAF3 stabilization and type I interferon production (By similarity).PTM (Microbial infection) Cleaved by enterovirus D68 protease 2A; leading to inhibition of NF-kappa-B or IFN-beta triggered by TRAF3.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt Q13114 1 EQUAL 568 EQUAL Reactome Database ID Release 82 914241 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=914241 Reactome R-HSA-914241 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-914241.1 2 viral dsRNA:TLR3:TRIF viral dsRNA:TLR3:TICAM1 Reactome DB_ID: 168907 TRIF TICAM1 Reactome DB_ID: 450316 UniProt:Q8IUC6 TICAM1 TICAM1 PRVTIRB 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 pro-inflammatory 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 pro-inflammatory 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 Database ID Release 82 450316 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=450316 Reactome R-HSA-450316 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-450316.1 2 viral dsRNA :TLR3 Reactome DB_ID: 167985 TLR3 Toll-like Receptor 3 Reactome DB_ID: 2000341 UniProt:O15455 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 Reactome Database ID Release 82 2000341 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=2000341 Reactome R-HSA-2000341 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-2000341.1 2 Converted from EntitySet in Reactome TLR3 ligand Reactome DB_ID: 9038432 Rotavirus dsRNA Reactome DB_ID: 8982440 endosome lumen GENE ONTOLOGY GO:0031904 Reactome Database ID Release 82 8982440 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=8982440 Reactome R-ROT-8982440 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-ROT-8982440.2 ChEBI 33697 additional information MI MI:0361 viral double-stranded RNA HSV1 dsRNA intermediate form HSV1 dsRNA replicative intermediate form Reactome DB_ID: 6791257 Reactome Database ID Release 82 6791257 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=6791257 Reactome R-HER-6791257 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-HER-6791257.1 ChEBI 67208 viral double-stranded RNA HCV dsRNA intermediate form HCV dsRNA replicative intermediate form Reactome DB_ID: 8982462 Reactome Database ID Release 82 8982462 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=8982462 Reactome R-HCV-8982462 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-HCV-8982462.2 ChEBI 67208 viral double-stranded RNA HBV dsRNA intermediate form HBV dsRNA replicative intermediate form Reactome DB_ID: 8982481 Reactome Database ID Release 82 8982481 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=8982481 Reactome R-HBV-8982481 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-HBV-8982481.2 ChEBI 67208 FLUAV dsRNA Stranded Influenza A dsRNA intermediate form Reactome DB_ID: 9028895 Reactome Database ID Release 82 9028895 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=9028895 Reactome R-FLU-9028895 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-FLU-9028895.3 ChEBI 67208 Reactome Database ID Release 82 9038432 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=9038432 Reactome R-NUL-9038432 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-NUL-9038432.1 1 Reactome Database ID Release 82 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 1 Reactome Database ID Release 82 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 1 Reactome Database ID Release 82 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 K63polyUb-TRAF3:TRIF:activated TLR3 K63polyUb-TRAF3:TICAM1:activated TLR3 Reactome DB_ID: 9013989 K63polyUb-TRAF3 K63 polyubiquitinated TRAF3 Reactome DB_ID: 936402 ubiquitinylated lysine MOD MOD:01148 1 EQUAL 568 EQUAL Reactome Database ID Release 82 936402 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=936402 Reactome R-HSA-936402 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-936402.2 2 1 Reactome Database ID Release 82 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 ACTIVATION activeUnit: #Protein16 GENE ONTOLOGY GO:0004842 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 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 82 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 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