Toll Like Receptor 3 (TLR3) Cascade (Homo sapiens)

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7, 8, 63634, 37, 54, 653647, 82, 8530, 46, 79, 8252, 69, 8132, 8049, 5736, 8815, 25, 34, 37, 54...6, 16, 774738, 44, 49, 53, 899, 2911, 30, 36, 47682813, 56, 6424, 28, 44, 4970, 8410, 80, 8414, 27, 34, 37, 41...2045, 47nucleoplasmcytosolendosomeUBB(77-152) RIP3:TICAM1:activated TLR3UBC(1-76) TLR3 HSV1 dsRNA intermediate form RIPK1 UBE2D2 Influenza A dsRNA intermediate form activatedTLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7TLR3 HSV1 dsRNA intermediate form UBC(609-684) p-S477,S479-IRF7 TLR3 ligandK63polyUbK63polyUb-TRAF3 p-S172-IKBKE UBC(153-228) RIPK3 ApoptosisTAB2 UBC(305-380) TICAM1 Influenza A dsRNA intermediate form HCV dsRNA intermediate form TAB3 Influenza A dsRNA intermediate form Influenza A dsRNA intermediate form Rotavirus dsRNA p-4S,T404-IRF3 HCV dsRNA intermediate form Rotavirus dsRNA HBV dsRNA intermediate form Influenza A dsRNA intermediate form FADD TICAM1 RPS27A(1-76) UBE2D3 CASP8(217-374) UBC(609-684) UBC(533-608) IKK related kinasesTBK1/IKK epsilonHCV dsRNA intermediate form HCV dsRNA intermediate form TAB3 Rotavirus dsRNA Rotavirus dsRNA UBA52(1-76) HCV dsRNA intermediate form IKBKG HCV dsRNA intermediate form TICAM1p-T184,T187-MAP3K7 HSV1 dsRNA intermediate form UBE2N RIPK1 UBC(77-152) HSV1 dsRNA intermediate form p-S477,S479-IRF7 UBB(153-228) TANKHCV dsRNA intermediate form HBV dsRNA intermediate form CASP8(1-479)HSV1 dsRNA intermediate form Influenza A dsRNA intermediate form TRAF3TRAF6 p-4S,T404-IRF3 UbMAP3K7 HCV dsRNA intermediate form TICAM1 UBC(229-304) viraldsRNA:TLR3:TRIF:TRAF6UBC(153-228) p-4S,T404-IRF3 HBV dsRNA intermediate form HSV1 dsRNA intermediate form TAB1 p-S172-IKBKE TICAM1 UBA52(1-76) TLR3 viraldsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1Rotavirus dsRNA TAB1 Rotavirus dsRNA Influenza A dsRNA intermediate form UBC(609-684) Influenza A dsRNA intermediate form Rotavirus dsRNA UBE2D1 viral dsRNA :TLR3TLR3 HSV1 dsRNA intermediate form HCV dsRNA intermediate form HSV1 dsRNA intermediate form TICAM1 Rotavirus dsRNA Rotavirus dsRNA HBV dsRNA intermediate form Regulated NecrosisTAB3 UBC(381-456) SARM-1ADPUBB(153-228) K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNATAB2 HBV dsRNA intermediate form HBV dsRNA intermediate form HSV1 dsRNA intermediate form K63polyUb-TRAF3 TLR3 TAK1 activates NFkBby phosphorylationand activation ofIKKs complexK63polyUbTRAF3 K63polyUb-TRAF3 TICAM1:activatedTLR3 complexesHSV1 dsRNA intermediate form HCV dsRNA intermediate form TICAM1 UBB(77-152) TICAM1 TICAM1 ADPTBK1 SARM-1 TLR3 p-S172-TBK1 active caspase-8TICAM1 IRF3 K63polyUb-TANK UBC(229-304) HCV dsRNA intermediate form Rotavirus dsRNA Rotavirus dsRNA CASP8(1-479) IKBKB p-S477,S479-IRF7 TLR3 HBV dsRNA intermediate form Rotavirus dsRNA ATPK63polyUb-TANK HBV dsRNA intermediate form p-S172-TBK1 HCV dsRNA intermediate form HBV dsRNA intermediate form BIRC3 viraldsRNA:TLR3:TICAM1:K63pUb-TRAF6HCV dsRNA intermediate form HBV dsRNA intermediate form HSV1 dsRNA intermediate form TLR3 FADD activatedTLR3:TRIF:RIP1:FADDHBV dsRNA intermediate form TICAM1 RIPK1RIPK1 TLR3 TICAM1 IKBKE TRAF3:TICAM1:viraldsRNA:TLR3Influenza A dsRNA intermediate form phosphorylated IRF3and/or IRF7 dimerHCV dsRNA intermediate form TLR3 Influenza A dsRNA intermediate form CASP8(385-479) viraldsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainHSV1 dsRNA intermediate form Influenza A dsRNA intermediate form Rotavirus dsRNA IKBKG K63polyUb-TRAF3 UbHCV dsRNA intermediate form HBV dsRNA intermediate form HBV dsRNA intermediate form K63polyUb-RIPK1 K63polyUb-TRAF3:TICAM1:activated TLR3UBE2V1 HBV dsRNA intermediate form K63polyUb-TANK TRAF6HBV dsRNA intermediate form K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1viraldsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKGBIRC2 UBB(1-76) K63polyUb-TRAF6 IRF7 TANK UBB(77-152) Influenza A dsRNA intermediate form TAB2 Influenza A dsRNA intermediate form UBC(153-228) TAB2 TICAM1 MAP kinaseactivationHSV1 dsRNA intermediate form Influenza A dsRNA intermediate form activatedTLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiCHUK Influenza A dsRNA intermediate form HBV dsRNA intermediate form TAB1:TAB2,TAB3:TAK1Influenza A dsRNA intermediate form HBV dsRNA intermediate form ATPTLR3 HSV1 dsRNA intermediate form K63polyUb K63polyUb-RIPK1 RIP1 ubiqutinligasesRIPK1 HCV dsRNA intermediate form viraldsRNA:TLR3:TICAM1ADPTICAM1 TAB3 activatedTLR3:TICAM1:K63pUb-RIP1IRF7 TLR3UBC(1-76) K63polyUb-TRAF6 UBC(457-532) SARM:TICAM1:viraldsRNA:TLR3viraldsRNA:TLR3:TICAM1:RIPK1HCV dsRNA intermediate form CHUK HSV1 dsRNA intermediate form UBB(1-76) Influenza A dsRNA intermediate form Rotavirus dsRNA HCV dsRNA intermediate form UBC(1-76) UBB(153-228) TAB1 TLR3 UBC(533-608) TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3Influenza A dsRNA intermediate form TLR3 HCV dsRNA intermediate form FADDTICAM1 TLR3 HSV1 dsRNA intermediate form HSV1 dsRNA intermediate form TLR3 K63polyUb-TRAF6 phosphorylated IRF3and/or IRF7 dimerCHUK:IKBKB:IKBKGTLR3 HBV dsRNA intermediate form K63polyUb-TRAF3 Rotavirus dsRNA RPS27A(1-76) UBC(305-380) Rotavirus dsRNA UBC(77-152) Rotavirus dsRNA RPS27A(1-76) TLR3 TLR3 UBC(457-532) HBV dsRNA intermediate form UBB(1-76) TRAF6 Rotavirus dsRNA UBC(457-532) UBC(381-456) HBV dsRNA intermediate form TICAM1 TLR3 HBV dsRNA intermediate form RIPK3K63polyUb Rotavirus dsRNA UBC(305-380) UBC(77-152) HCV dsRNA intermediate form HSV1 dsRNA intermediate form UBA52(1-76) Influenza A dsRNA intermediate form p-T184,T187-MAP3K7 TICAM1 TICAM1 IRF3 TICAM1 K63polyUb p-4S,T404-IRF3,p-S477,S479-IRF7activatedTLR3:TRIF:RIP1:FADD:pro-caspase-8TAB1 ATPMAP3K7 IRF3,IRF7Influenza A dsRNA intermediate form TICAM1 HSV1 dsRNA intermediate form UBC(381-456) TLR3 K63polyUb-TRAF6 HSV1 dsRNA intermediate form UBC(533-608) Rotavirus dsRNA RIPK1 HSV1 dsRNA intermediate form UBC(229-304) HCV dsRNA intermediate form Influenza A dsRNA intermediate form Rotavirus dsRNA IKBKB 6834, 70, 844343354368431, 8734, 70, 8449, 7016, 772, 16, 8335, 52, 70, 778034, 70, 845, 12, 22, 71, 72, 74...4316, 7743594343684321, 5859204334, 54433, 19, 23, 26, 33...438043434, 39, 42436843251, 55, 75434348, 625934, 54, 70, 7617, 18, 31, 6143438643


Toll-like receptor 3 (TLR3) as was shown for mammals is expressed on myeloid dendritic cells, respiratory epithelium, macrophages, and appears to play a central role in mediating the antiviral and inflammatory responses of the innate immunity in combating viral infections.

Mammalian TLR3 recognizes dsRNA, and that triggers the receptor to induce the activation of NF-kappaB and the production of type I interferons (IFNs). dsRNA-stimulated phosphorylation of two specific TLR3 tyrosine residues (Tyr759 and Tyr858) is essential for initiating TLR3 signaling pathways. View original pathway at Reactome.</div>


Pathway is converted from Reactome ID: 168164
Reactome version: 73
Reactome Author 
Reactome Author: Luo, F

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  1. Thiefes A, Wolter S, Mushinski JF, Hoffmann E, Dittrich-Breiholz O, Graue N, Dörrie A, Schneider H, Wirth D, Luckow B, Resch K, Kracht M.; ''Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes.''; PubMed Europe PMC Scholia
  2. Huang J, Liu T, Xu LG, Chen D, Zhai Z, Shu HB.; ''SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways.''; PubMed Europe PMC Scholia
  3. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, Picard C, Chapgier A, Plancoulaine S, Titeux M, Cognet C, von Bernuth H, Ku CL, Casrouge A, Zhang XX, Barreiro L, Leonard J, Hamilton C, Lebon P, Héron B, Vallée L, Quintana-Murci L, Hovnanian A, Rozenberg F, Vivier E, Geissmann F, Tardieu M, Abel L, Casanova JL.; ''TLR3 deficiency in patients with herpes simplex encephalitis.''; PubMed Europe PMC Scholia
  4. Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed Europe PMC Scholia
  5. Adams JM.; ''Ways of dying: multiple pathways to apoptosis.''; PubMed Europe PMC Scholia
  6. Tseng PH, Matsuzawa A, Zhang W, Mino T, Vignali DA, Karin M.; ''Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines.''; PubMed Europe PMC Scholia
  7. Sen GC, Sarkar SN.; ''Transcriptional signaling by double-stranded RNA: role of TLR3.''; PubMed Europe PMC Scholia
  8. Carpenter S, O'Neill LA.; ''Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins.''; PubMed Europe PMC Scholia
  9. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA.; ''Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.''; PubMed Europe PMC Scholia
  10. Bertrand MJ, Lippens S, Staes A, Gilbert B, Roelandt R, De Medts J, Gevaert K, Declercq W, Vandenabeele P.; ''cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).''; PubMed Europe PMC Scholia
  11. Larabi A, Devos JM, Ng SL, Nanao MH, Round A, Maniatis T, Panne D.; ''Crystal structure and mechanism of activation of TANK-binding kinase 1.''; PubMed Europe PMC Scholia
  12. MacFarlane M, Williams AC.; ''Apoptosis and disease: a life or death decision.''; PubMed Europe PMC Scholia
  13. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S.; ''Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.''; PubMed Europe PMC Scholia
  14. Keller N, Mares J, Zerbe O, Grütter MG.; ''Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation.''; PubMed Europe PMC Scholia
  15. Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, Zachariou A, Lopez J, MacFarlane M, Cain K, Meier P.; ''The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs.''; PubMed Europe PMC Scholia
  16. Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng G.; ''Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.''; PubMed Europe PMC Scholia
  17. Banerjee A, Gerondakis S.; ''Coordinating TLR-activated signaling pathways in cells of the immune system.''; PubMed Europe PMC Scholia
  18. Bardwell AJ, Frankson E, Bardwell L.; ''Selectivity of docking sites in MAPK kinases.''; PubMed Europe PMC Scholia
  19. Li K, Li NL, Wei D, Pfeffer SR, Fan M, Pfeffer LM.; ''Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.''; PubMed Europe PMC Scholia
  20. Carty M, Goodbody R, Schröder M, Stack J, Moynagh PN, Bowie AG.; ''The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling.''; PubMed Europe PMC Scholia
  21. Leonard JN, Ghirlando R, Askins J, Bell JK, Margulies DH, Davies DR, Segal DM.; ''The TLR3 signaling complex forms by cooperative receptor dimerization.''; PubMed Europe PMC Scholia
  22. Kerr JF.; ''History of the events leading to the formulation of the apoptosis concept.''; PubMed Europe PMC Scholia
  23. Rong Y, Song H, You S, Zhu B, Zang H, Zhao Y, Li Y, Wan Z, Liu H, Zhang A, Xiao L, Xin S.; ''Association of Toll-like receptor 3 polymorphisms with chronic hepatitis B and hepatitis B-related acute-on-chronic liver failure.''; PubMed Europe PMC Scholia
  24. Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A, Chiu YH, Deng L, Chen ZJ.; ''TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains.''; PubMed Europe PMC Scholia
  25. Creagh EM, Conroy H, Martin SJ.; ''Caspase-activation pathways in apoptosis and immunity.''; PubMed Europe PMC Scholia
  26. Ebihara T, Shingai M, Matsumoto M, Wakita T, Seya T.; ''Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells.''; PubMed Europe PMC Scholia
  27. Oberst A, Pop C, Tremblay AG, Blais V, Denault JB, Salvesen GS, Green DR.; ''Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation.''; PubMed Europe PMC Scholia
  28. Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ.; ''Direct activation of protein kinases by unanchored polyubiquitin chains.''; PubMed Europe PMC Scholia
  29. Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR.; ''Structural basis of toll-like receptor 3 signaling with double-stranded RNA.''; PubMed Europe PMC Scholia
  30. Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, Kawai T, Hoshino K, Takeda K, Akira S.; ''The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection.''; PubMed Europe PMC Scholia
  31. Chang L, Karin M.; ''Mammalian MAP kinase signalling cascades.''; PubMed Europe PMC Scholia
  32. Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD.; ''Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected].''; PubMed Europe PMC Scholia
  33. Guillot L, Le Goffic R, Bloch S, Escriou N, Akira S, Chignard M, Si-Tahar M.; ''Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus.''; PubMed Europe PMC Scholia
  34. Kaiser WJ, Offermann MK.; ''Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif.''; PubMed Europe PMC Scholia
  35. Jiang Z, Mak TW, Sen G, Li X.; ''Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.''; PubMed Europe PMC Scholia
  36. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC Scholia
  37. Kalai M, Van Loo G, Vanden Berghe T, Meeus A, Burm W, Saelens X, Vandenabeele P.; ''Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA.''; PubMed Europe PMC Scholia
  38. Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS, Lee KY, Bussey C, Steckel M, Tanaka N, Yamada G, Akira S, Matsumoto K, Ghosh S.; ''TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo.''; PubMed Europe PMC Scholia
  39. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC Scholia
  40. Wang Y, Li J, Wang X, Zhou Y, Zhang T, Ho W.; ''HCV dsRNA-Activated Macrophages Inhibit HCV Replication in Hepatocytes.''; PubMed Europe PMC Scholia
  41. Donepudi M, Mac Sweeney A, Briand C, Grütter MG.; ''Insights into the regulatory mechanism for caspase-8 activation.''; PubMed Europe PMC Scholia
  42. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
  43. Son KN, Liang Z, Lipton HL.; ''Double-Stranded RNA Is Detected by Immunofluorescence Analysis in RNA and DNA Virus Infections, Including Those by Negative-Stranded RNA Viruses.''; PubMed Europe PMC Scholia
  44. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed Europe PMC Scholia
  45. Takahasi K, Suzuki NN, Horiuchi M, Mori M, Suhara W, Okabe Y, Fukuhara Y, Terasawa H, Akira S, Fujita T, Inagaki F.; ''X-ray crystal structure of IRF-3 and its functional implications.''; PubMed Europe PMC Scholia
  46. Lin R, Heylbroeck C, Pitha PM, Hiscott J.; ''Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation.''; PubMed Europe PMC Scholia
  47. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T.; ''IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.''; PubMed Europe PMC Scholia
  48. Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grütter MG.; ''The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.''; PubMed Europe PMC Scholia
  49. Jiang Z, Zamanian-Daryoush M, Nie H, Silva AM, Williams BR, Li X.; ''Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR .''; PubMed Europe PMC Scholia
  50. Wang B, Trippler M, Pei R, Lu M, Broering R, Gerken G, Schlaak JF.; ''Toll-like receptor activated human and murine hepatic stellate cells are potent regulators of hepatitis C virus replication.''; PubMed Europe PMC Scholia
  51. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P.; ''Regulated necrosis: the expanding network of non-apoptotic cell death pathways.''; PubMed Europe PMC Scholia
  52. Sasai M, Tatematsu M, Oshiumi H, Funami K, Matsumoto M, Hatakeyama S, Seya T.; ''Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathway.''; PubMed Europe PMC Scholia
  53. Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, Matsumoto K, Takeuchi O, Akira S.; ''Essential function for the kinase TAK1 in innate and adaptive immune responses.''; PubMed Europe PMC Scholia
  54. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Häcker G, Leverkus M.; ''cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms.''; PubMed Europe PMC Scholia
  55. Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N.; ''Crosstalk between apoptosis, necrosis and autophagy.''; PubMed Europe PMC Scholia
  56. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT.; ''LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF.''; PubMed Europe PMC Scholia
  57. Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K, Li X.; ''Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol.''; PubMed Europe PMC Scholia
  58. Botos I, Liu L, Wang Y, Segal DM, Davies DR.; ''The toll-like receptor 3:dsRNA signaling complex.''; PubMed Europe PMC Scholia
  59. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM.; ''FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.''; PubMed Europe PMC Scholia
  60. Lafaille FG, Pessach IM, Zhang SY, Ciancanelli MJ, Herman M, Abhyankar A, Ying SW, Keros S, Goldstein PA, Mostoslavsky G, Ordovas-Montanes J, Jouanguy E, Plancoulaine S, Tu E, Elkabetz Y, Al-Muhsen S, Tardieu M, Schlaeger TM, Daley GQ, Abel L, Casanova JL, Studer L, Notarangelo LD.; ''Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells.''; PubMed Europe PMC Scholia
  61. Dong C, Davis RJ, Flavell RA.; ''MAP kinases in the immune response.''; PubMed Europe PMC Scholia
  62. Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD.; ''The atomic-resolution structure of human caspase-8, a key activator of apoptosis.''; PubMed Europe PMC Scholia
  63. Vercammen E, Staal J, Beyaert R.; ''Sensing of viral infection and activation of innate immunity by toll-like receptor 3.''; PubMed Europe PMC Scholia
  64. Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T.; ''TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction.''; PubMed Europe PMC Scholia
  65. He S, Liang Y, Shao F, Wang X.; ''Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway.''; PubMed Europe PMC Scholia
  66. Pott J, Stockinger S, Torow N, Smoczek A, Lindner C, McInerney G, Bäckhed F, Baumann U, Pabst O, Bleich A, Hornef MW.; ''Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility.''; PubMed Europe PMC Scholia
  67. Han KJ, Su X, Xu LG, Bin LH, Zhang J, Shu HB.; ''Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways.''; PubMed Europe PMC Scholia
  68. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMed Europe PMC Scholia
  69. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ.; ''Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.''; PubMed Europe PMC Scholia
  70. Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA.; ''Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.''; PubMed Europe PMC Scholia
  71. Cory S, Adams JM.; ''The Bcl2 family: regulators of the cellular life-or-death switch.''; PubMed Europe PMC Scholia
  72. Cory S, Huang DC, Adams JM.; ''The Bcl-2 family: roles in cell survival and oncogenesis.''; PubMed Europe PMC Scholia
  73. Hidaka F, Matsuo S, Muta T, Takeshige K, Mizukami T, Nunoi H.; ''A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy.''; PubMed Europe PMC Scholia
  74. Kerr JF, Wyllie AH, Currie AR.; ''Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.''; PubMed Europe PMC Scholia
  75. Mocarski ES, Kaiser WJ, Livingston-Rosanoff D, Upton JW, Daley-Bauer LP.; ''True grit: programmed necrosis in antiviral host defense, inflammation, and immunogenicity.''; PubMed Europe PMC Scholia
  76. Estornes Y, Toscano F, Virard F, Jacquemin G, Pierrot A, Vanbervliet B, Bonnin M, Lalaoui N, Mercier-Gouy P, Pachéco Y, Salaun B, Renno T, Micheau O, Lebecque S.; ''dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8.''; PubMed Europe PMC Scholia
  77. Häcker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Häcker G, Mann M, Karin M.; ''Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.''; PubMed Europe PMC Scholia
  78. Ashkenazi A.; ''Targeting death and decoy receptors of the tumour-necrosis factor superfamily.''; PubMed Europe PMC Scholia
  79. An H, Zhao W, Hou J, Zhang Y, Xie Y, Zheng Y, Xu H, Qian C, Zhou J, Yu Y, Liu S, Feng G, Cao X.; ''SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production.''; PubMed Europe PMC Scholia
  80. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ.; ''Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO.''; PubMed Europe PMC Scholia
  81. Walsh MC, Kim GK, Maurizio PL, Molnar EE, Choi Y.; ''TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL.''; PubMed Europe PMC Scholia
  82. Mori M, Yoneyama M, Ito T, Takahashi K, Inagaki F, Fujita T.; ''Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation.''; PubMed Europe PMC Scholia
  83. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S.; ''Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling.''; PubMed Europe PMC Scholia
  84. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J.; ''RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.''; PubMed Europe PMC Scholia
  85. Panne D, McWhirter SM, Maniatis T, Harrison SC.; ''Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch.''; PubMed Europe PMC Scholia
  86. Gatot JS, Gioia R, Chau TL, Patrascu F, Warnier M, Close P, Chapelle JP, Muraille E, Brown K, Siebenlist U, Piette J, Dejardin E, Chariot A.; ''Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF.''; PubMed Europe PMC Scholia
  87. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC Scholia
  88. Guo B, Cheng G.; ''Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK.''; PubMed Europe PMC Scholia
  89. Kishimoto K, Matsumoto K, Ninomiya-Tsuji J.; ''TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.''; PubMed Europe PMC Scholia


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112469view15:42, 9 October 2020ReactomeTeamReactome version 73
101378view11:26, 1 November 2018ReactomeTeamreactome version 66
100916view21:01, 31 October 2018ReactomeTeamreactome version 65
100457view19:36, 31 October 2018ReactomeTeamreactome version 64
100004view16:20, 31 October 2018ReactomeTeamreactome version 63
99557view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99186view12:42, 31 October 2018ReactomeTeamreactome version 62
93762view13:34, 16 August 2017ReactomeTeamreactome version 61
93286view11:19, 9 August 2017ReactomeTeamreactome version 61
88401view15:21, 4 August 2016FehrhartOntology Term : 'Toll-like receptor signaling pathway' added !
86370view09:16, 11 July 2016ReactomeTeamreactome version 56
83334view10:49, 18 November 2015ReactomeTeamVersion54
81488view13:01, 21 August 2015ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
ApoptosisPathwayR-HSA-109581 (Reactome) Apoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and membrane blebbing characterize apoptosis in general. Mitochondria remain morphologically unchanged. In 1972 Kerr et al introduced the concept of apoptosis as a distinct form of "cell-death", and the mechanisms of various apoptotic pathways are still being revealed today.
The two principal pathways of apoptosis are (1) the Bcl-2 inhibitable or intrinsic pathway induced by various forms of stress like intracellular damage, developmental cues, and external stimuli and (2) the caspase 8/10 dependent or extrinsic pathway initiated by the engagement of death receptors
The caspase 8/10 dependent or extrinsic pathway is a death receptor mediated mechanism that results in the activation of caspase-8 and caspase-10. Activation of death receptors like Fas/CD95, TNFR1, and the TRAIL receptor is promoted by the TNF family of ligands including FASL (APO1L OR CD95L), TNF, LT-alpha, LT-beta, CD40L, LIGHT, RANKL, BLYS/BAFF, and APO2L/TRAIL. These ligands are released in response to microbial infection, or as part of the cellular, humoral immunity responses during the formation of lymphoid organs, activation of dendritic cells, stimulation or survival of T, B, and natural killer (NK) cells, cytotoxic response to viral infection or oncogenic transformation.
The Bcl-2 inhibitable or intrinsic pathway of apoptosis is a stress-inducible process, and acts through the activation of caspase-9 via Apaf-1 and cytochrome c. The rupture of the mitochondrial membrane, a rapid process involving some of the Bcl-2 family proteins, releases these molecules into the cytoplasm. Examples of cellular processes that may induce the intrinsic pathway in response to various damage signals include: auto reactivity in lymphocytes, cytokine deprivation, calcium flux or cellular damage by cytotoxic drugs like taxol, deprivation of nutrients like glucose and growth factors like EGF, anoikis, transactivation of target genes by tumor suppressors including p53.
In many non-immune cells, death signals initiated by the extrinsic pathway are amplified by connections to the intrinsic pathway. The connecting link appears to be the truncated BID (tBID) protein a proteolytic cleavage product mediated by caspase-8 or other enzymes.
BIRC2 ProteinQ13490 (Uniprot-TrEMBL)
BIRC3 ProteinQ13489 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479)ProteinQ14790 (Uniprot-TrEMBL)
CASP8(217-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(385-479) ProteinQ14790 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
HBV dsRNA intermediate form R-HBV-8982481 (Reactome)
HCV dsRNA intermediate form R-HCV-8982462 (Reactome)
HSV1 dsRNA intermediate form R-HER-6791257 (Reactome)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKE ProteinQ14164 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKK related kinases TBK1/IKK epsilonComplexR-HSA-450329 (Reactome)
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF3,IRF7ComplexR-HSA-450317 (Reactome)
IRF7 ProteinQ92985 (Uniprot-TrEMBL)
Influenza A dsRNA intermediate form R-FLU-9028895 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNAComplexR-HSA-9013976 (Reactome)
K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1ComplexR-HSA-847073 (Reactome)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb R-HSA-450271 (Reactome)
K63polyUb-RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
K63polyUb-TANK ProteinQ92844 (Uniprot-TrEMBL)
K63polyUb-TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
K63polyUb-TRAF3:TICAM1:activated TLR3ComplexR-HSA-9013989 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
MAP kinase activationPathwayR-HSA-450294 (Reactome) The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002).

There are three major groups of MAP kinases

  • the extracellular signal-regulated protein kinases ERK1/2,
  • the p38 MAP kinase
  • and the c-Jun NH-terminal kinases JNK.

ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).

MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.

The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.

The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear.

MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
RIP1 ubiqutin ligasesComplexR-HSA-2569050 (Reactome)
RIP3:TICAM1:activated TLR3ComplexR-HSA-9013956 (Reactome)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
RIPK3 ProteinQ9Y572 (Uniprot-TrEMBL)
RIPK3ProteinQ9Y572 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Regulated NecrosisPathwayR-HSA-5218859 (Reactome) Necrosis has traditionally been considered as a passive, unregulated cell death. However, accumulating evidence suggests that necrosis, like apoptosis, can be executed by genetically controlled and highly regulated cellular process that is morphologically characterized by a loss of cell membrane integrity, intracellular organelles and/or the entire cell swelling (oncosis) (Rello S et al. 2005; Galluzzi L et al. 2007; Berghe TV et al. 2014; Ros U et al. 2020). The morphological hallmarks of the nectotic death have been associated with different forms of programmed cell death including (but not limited to) parthanatos, necroptosis, glutamate-induced oxytosis, ferroptosis, inflammasome-mediated necrosis etc. Each of them can be triggered under certain pathophysiological conditions. For example UV, ROS or alkylating agents may induce poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation (parthanatos), while tumor necrosis factor (TNF) or toll like receptor ligands (LPS and dsRNA) can trigger necrosome-mediated necroptosis. The initiation events, e.g., PARP1 hyperactivation, necrosome formation, activation of NADPH oxidases, in turn trigger one or several common intracellular signals such as NAD+ and ATP-depletion, enhanced Ca2+ influx, dysregulation of the redox status, increased production of reactive oxygen species (ROS) and the activity of phospholipases. These signals affect cellular organelles and membranes leading to osmotic swelling, massive energy depletion, lipid peroxidation and the loss of lysosomal membrane integrity. Different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Regulated or programmed necrosis eventually leads to cell lysis and release of cytoplasmic content into the extracellular region that is often associated with a tissue damage resulting in an intense inflammatory response.

The Reactome module describes necroptosis as the most characterized form of regulated necrosis. The molecular mechanisms behind the other types of regulated necrosis as well as interconnectivity among them need further studies.

Rotavirus dsRNA R-ROT-8982440 (Reactome)
SARM-1 ProteinQ6SZW1-1 (Uniprot-TrEMBL)
SARM-1ProteinQ6SZW1-1 (Uniprot-TrEMBL)
SARM:TICAM1:viral dsRNA:TLR3ComplexR-HSA-9014322 (Reactome)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB1:TAB2,TAB3:TAK1ComplexR-HSA-450277 (Reactome)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 activates NFkB

by phosphorylation and activation of

IKKs complex
PathwayR-HSA-445989 (Reactome) NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression.
TANK ProteinQ92844 (Uniprot-TrEMBL)
TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3ComplexR-HSA-9013980 (Reactome)
TANKProteinQ92844 (Uniprot-TrEMBL)
TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TICAM1:activated TLR3 complexesComplexR-HSA-9013962 (Reactome)
TICAM1ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR3 ligandComplexR-NUL-9038432 (Reactome)
TLR3ProteinO15455 (Uniprot-TrEMBL)
TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
TRAF3:TICAM1:viral dsRNA:TLR3ComplexR-HSA-9013984 (Reactome)
TRAF3ProteinQ13114 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2D3 ProteinP61077 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
activated TLR3:TICAM1:K63pUb-RIP1ComplexR-HSA-9014344 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7ComplexR-HSA-9013981 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiComplexR-HSA-9013982 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8ComplexR-HSA-9013891 (Reactome)
activated TLR3:TRIF:RIP1:FADDComplexR-HSA-9013893 (Reactome)
active caspase-8ComplexR-HSA-2562550 (Reactome)
p-4S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-4S,T404-IRF3,p-S477,S479-IRF7ComplexR-HSA-450240 (Reactome)
p-S172-IKBKE ProteinQ14164 (Uniprot-TrEMBL)
p-S172-TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
p-S477,S479-IRF7 ProteinQ92985 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
phosphorylated IRF3 and/or IRF7 dimerComplexR-HSA-450256 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerComplexR-HSA-450349 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKGComplexR-HSA-9014341 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6ComplexR-HSA-450309 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1ComplexR-HSA-177649 (Reactome)
viral dsRNA:TLR3:TICAM1ComplexR-HSA-168907 (Reactome)
viral dsRNA:TLR3:TRIF:TRAF6ComplexR-HSA-177693 (Reactome)
viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1ComplexR-HSA-177691 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainComplexR-HSA-177689 (Reactome)
viral dsRNA :TLR3ComplexR-HSA-167985 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-177692 (Reactome)
ADPArrowR-HSA-9013978 (Reactome)
ADPArrowR-HSA-9013986 (Reactome)
ATPR-HSA-177692 (Reactome)
ATPR-HSA-9013978 (Reactome)
ATPR-HSA-9013986 (Reactome)
CASP8(1-479)R-HSA-9013889 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-9014343 (Reactome)
FADDR-HSA-9013889 (Reactome)
IKK related kinases TBK1/IKK epsilonR-HSA-9013986 (Reactome)
IRF3,IRF7R-HSA-9013979 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNAArrowR-HSA-9013990 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNAR-HSA-9013986 (Reactome)
K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1ArrowR-HSA-847070 (Reactome)
K63polyUb-TRAF3:TICAM1:activated TLR3ArrowR-HSA-9013974 (Reactome)
K63polyUb-TRAF3:TICAM1:activated TLR3R-HSA-9013985 (Reactome)
K63polyUbArrowR-HSA-9628444 (Reactome)
K63polyUbR-HSA-177690 (Reactome)
K63polyUbR-HSA-9014342 (Reactome)
R-HSA-168092 (Reactome) Viral dsRNA triggers an antiviral pathway mediated by toll like receptor 3. TLR3 dimerization occurs upon ligand binding to positivly charged residues on the ectodomain termini of TLR3 wich are responsible for the interaction with sugar-phosphate groups of dsRNA.
R-HSA-168929 (Reactome) TIR-domain-containing adaptor inducing interferon-beta (TRIF or TICAM1) was shown to play an essential role in TLR3 signaling. All poly(I:C)-induced pathways leading to NFkB and IRF3 activation were abolished in TRIF-/- mice [Yamamoto et al. 2003].
R-HSA-168930 (Reactome) RIP1 is recruited to the activated TLR receptor by binding to TICAM1(TRIF) via its RHIM motif, followed by its polyubiquitination. Polyubiquitination is possibly mediated by TRAF6 that is also recruited to TICAM1 (Cusson-Hermance N et al. 2005). Other E3-ubiquitin ligases - cIAP1 and cIAP2 - have been reported to promote polyubiquitination of RIP proteins (Bertrand MJM et al. 2011).

RIP3 was shown to inhibit TRIF-induced NFkB activation in dose-dependent manner when overexpressed in HEK293T cells by competing with TRIF to bind RIP1 (Meylan E et al. 2004).

R-HSA-168933 (Reactome) Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300.
R-HSA-177671 (Reactome) IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm.
R-HSA-177690 (Reactome) TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.This binding leads to autophosphorylation and activation of TAK1.
R-HSA-177692 (Reactome) TAK1 complex consists of transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).
R-HSA-177694 (Reactome) TRAF6 is recruited to the N-terminal domain of TICAM1 and this event is followed by auto polyubiquitination and oligomerization of TRAF6.
R-HSA-450259 (Reactome) TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
R-HSA-847070 (Reactome) Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol
R-HSA-9013889 (Reactome) TRIF (also known as TICAM1) was repored to efficiently induce apoptosis when overexpressed in human HEK293T cells. TRIF-induced apoptosis occurred through activation of the FADD-caspase-8 axis (Kaiser WJ and Offermann MK 2005; Kalai M et al. 2002; Estornes Y et al. 2012). C-terminus of TRIF was shown to form complexes with both RIP1 and RIP3, and disruption of these interactions by mutating the RHIM eliminated the ability of TRIF to induce apoptosis (Kaiser WJ and Offermann MK 2005).

Prevention of RIP1 ubiquitination leads to a strong association of RIP1 and caspase-8 (Feoktistova M et al. 2011, Tenev et al. 2011).

R-HSA-9013895 (Reactome) TLR3 and TLR4 were shown to mediate apoptosis in various human cell lines in the FADD:caspasse-8-dependent manner (Kalai M et al. 2002; Kaiser WJ and Offermann MK 2005; Estornes Y et al. 2012). Caspase-8 zymogens (procaspase-8) are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region (Donepudi M et al. 2003; Keller N et al. 2009). Dimerization is required for caspase-8 activation (Donepudi M et al. 2003). The dimerization event occurs at the receptor signaling complex. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is compsed of a large p18 and a small p10 subunit (Keller N et al. 2009; Oberst A et al. 2010).
R-HSA-9013963 (Reactome) TLR3 and TLR4 -directed programmed necrosis (necroptosis) is mediated by the TRIF-RIP3 pathway in mouse macrophages [He S e al 2011]. RIP3 was shown to be essential mediator in TLR3-induced necroptotic cell death in human epithelial cell lines. Knockdown of RIP3 in human keratinocyte HaCaT cells blocked TLR3-mediated necroptosis without affecting the apoptotic response. Moreover, overexpression of RIP3 in human epithelial carcinoma cell line HeLa led to increased caspase-independent TLR3-induced cell death in the absence of IAPs [Feoktistova M et al 2011]. In addition, in caspase-8- or FADD-deficient human Jurkat cells dsRNA induced programmed necrosis, instead of apoptosis [Kalai M et al 2002]. Thus, when caspase-dependent apoptosis is inhibited or absent, the alternative RIP3-mediated programmed cell death is induced.
R-HSA-9013974 (Reactome) 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).
R-HSA-9013978 (Reactome) 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.

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).

R-HSA-9013979 (Reactome) 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).
R-HSA-9013985 (Reactome) 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).

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).

R-HSA-9013986 (Reactome) 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).
R-HSA-9013990 (Reactome) 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.
R-HSA-9013992 (Reactome) 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].
R-HSA-9014320 (Reactome) SARM (sterile alpha-and armadillo-motif-containing protein) is a TIR-domain-containing adaptor, which functions as a negative regulator of TRIF (TICAM1)-dependent Toll-like receptor signaling in humans. A pairwise yeast two-hybrid assay demonstrated that SARM is capable of binding directly to TICAM1 (Carty M et al. 2006). GST pulldown studies suggest that protein-protein interactions occur between the TIR domains of SARM and TICAM1 (Carlsson E et al. 2016). The complex of TICAM1:SARM is thought to inhibit downstream TRIF signaling by preventing the recruitment of TRIF effector proteins (Carty M et al. 2006).

SARM expression was shown to inhibit poly(I:C)-induced TICAM1-dependent NFkappaB activaion, RANTES production and IRF activation in human embryonic kidney HEK293 cells (Carty M et al. 2006). Moreover, suppression of endogenous SARM expression by siRNA led to enhanced TLR3- and TLR4-dependent gene induction in both transformed HEK293 and primary PBMC cells (Carty M et al. 2006), Thus, SARM associates with TICAM1 via its TIR and sterile-alpha motif (SAM) domains to block the induction of proinflammatory genes downstream TLR3.

R-HSA-9014342 (Reactome) RIP1 polyubiquitination was induced upon TNF- or poly(I-C) treatment of the macrophage cell line RAW264.7 and the U373 astrocytoma line (Cusson-Hermance et al 2005). These workers have suggested that RIP1 may use similar mechanisms to induce NF-kB in the TNFR1- and Trif-dependent TLR pathways.

RIP1 modification with Lys-63 polyubiquitin chains was shown to be essential for TNF-induced activation of NF-kB (Ea et al. 2006). It is thought that TRAF family members mediate this Lys63-linked ubiquitination of RIP1 (Wertz et al. 2004, Tada et al 2001, Vallabhapurapu and Karin 2009), which may facilitate recruitment of the TAK1 complex and thus activation of NF-kB. Binding of NEMO to Lys63-linked polyubiquitinated RIP1 is also required in the signaling cascade from the activated receptor to the IKK-mediated NF-kB activation (Wu et al. 2006).

R-HSA-9014343 (Reactome) Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation.
R-HSA-9628444 (Reactome) E3 ubiquitin ligase TRAF6 generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase.
RIP1 ubiqutin ligasesmim-catalysisR-HSA-9014342 (Reactome)
RIP3:TICAM1:activated TLR3ArrowR-HSA-9013963 (Reactome)
RIPK1R-HSA-168930 (Reactome)
RIPK3R-HSA-9013963 (Reactome)
RIPK3TBarR-HSA-168930 (Reactome)
SARM-1R-HSA-9014320 (Reactome)
SARM:TICAM1:viral dsRNA:TLR3ArrowR-HSA-9014320 (Reactome)
TAB1:TAB2,TAB3:TAK1R-HSA-177690 (Reactome)
TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3ArrowR-HSA-9013985 (Reactome)
TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3R-HSA-9013990 (Reactome)
TANKR-HSA-9013985 (Reactome)
TICAM1:activated TLR3 complexesR-HSA-9013963 (Reactome)
TICAM1R-HSA-168929 (Reactome)
TLR3 ligandR-HSA-168092 (Reactome)
TLR3R-HSA-168092 (Reactome)
TRAF3:TICAM1:viral dsRNA:TLR3ArrowR-HSA-9013992 (Reactome)
TRAF3:TICAM1:viral dsRNA:TLR3R-HSA-9013974 (Reactome)
TRAF3:TICAM1:viral dsRNA:TLR3mim-catalysisR-HSA-9013974 (Reactome)
TRAF3R-HSA-9013992 (Reactome)
TRAF6R-HSA-177694 (Reactome)
UbR-HSA-450259 (Reactome)
UbR-HSA-9013974 (Reactome)
UbR-HSA-9013990 (Reactome)
UbR-HSA-9628444 (Reactome)
activated TLR3:TICAM1:K63pUb-RIP1ArrowR-HSA-9014342 (Reactome)
activated TLR3:TICAM1:K63pUb-RIP1R-HSA-9014343 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7ArrowR-HSA-9013979 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7R-HSA-9013978 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7mim-catalysisR-HSA-9013978 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiArrowR-HSA-9013978 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiArrowR-HSA-9013986 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiR-HSA-9013979 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8ArrowR-HSA-9013889 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8R-HSA-9013895 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8mim-catalysisR-HSA-9013895 (Reactome)
activated TLR3:TRIF:RIP1:FADDArrowR-HSA-9013895 (Reactome)
active caspase-8ArrowR-HSA-9013895 (Reactome)
p-4S,T404-IRF3,p-S477,S479-IRF7ArrowR-HSA-9013978 (Reactome)
p-4S,T404-IRF3,p-S477,S479-IRF7R-HSA-168933 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerArrowR-HSA-168933 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerArrowR-HSA-177671 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerR-HSA-177671 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKGArrowR-HSA-9014343 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6ArrowR-HSA-450259 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6R-HSA-177690 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6mim-catalysisR-HSA-9628444 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1ArrowR-HSA-168930 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1R-HSA-9013889 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1R-HSA-9014342 (Reactome)
viral dsRNA:TLR3:TICAM1ArrowR-HSA-168929 (Reactome)
viral dsRNA:TLR3:TICAM1ArrowR-HSA-847070 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-168930 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-177694 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-9013992 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-9014320 (Reactome)
viral dsRNA:TLR3:TRIF:TRAF6ArrowR-HSA-177694 (Reactome)
viral dsRNA:TLR3:TRIF:TRAF6R-HSA-450259 (Reactome)
viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1ArrowR-HSA-177692 (Reactome)
viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1R-HSA-847070 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainArrowR-HSA-177690 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainR-HSA-177692 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainmim-catalysisR-HSA-177692 (Reactome)
viral dsRNA :TLR3ArrowR-HSA-168092 (Reactome)
viral dsRNA :TLR3R-HSA-168929 (Reactome)

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