MyD88-independent TLR4 cascade (Homo sapiens)

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1024, 256, 3126, 558, 11, 54, 58, 6911, 23, 3036563, 28, 50, 6115, 6114, 28, 42, 59, 6141, 4741, 474834, 66, 68, 7119, 28, 50, 60, 61, 6429, 45, 46, 53, 611, 17, 5336, 7236, 47, 67, 6912, 48, 62126, 3835, 36, 54endosome lumennucleoplasmcytosolTAB1 TLR4 IRF7 TRAF6 LPS TLR4 CASP8(385-479) TICAM1 TLR4 UBB(77-152) phosphorylated IRF3and/or IRF7 dimeractivatedTLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7CASP8(1-479)MyrG-p-S16-TICAM2 UBE2D3 TRAF6FADD LPS GPIN-CD14(20-345) LY96 TICAM1 UBC(381-456) TICAM1 TLR4 UBB(153-228) p-S172-TBK1 TICAM1:TRAM:TLR4:LY96:LPS:CD14K63polyUb-TRAF6 UBA52(1-76) TICAM1 LY96 K63polyUb-TRAF3 K63-linked polyUbTRAF6 complexesHCV dsRNA intermediate form UBC(457-532) p-S477,S479-IRF7 MyrG-p-S16-TICAM2 TRAF6 GPIN-CD14(20-345) RIP1 ubiqutinligasesRIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14LPS LY96 GPIN-CD14(20-345) TLR4 RIPK1TAB2 MyrG-p-S16-TICAM2 LPS TAB2 FADD CHUK:IKBKB:IKBKG:K63pUb-RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14TICAM1 UBE2N UbTICAM1 K63-pUb-TRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14TICAM1p-4S,T404-IRF3 UBC(609-684) RIP3:TICAM1:activated TLR4UBC(533-608) ADPTLR4 HSV1 dsRNA intermediate form TICAM1 LPS LPS UBA52(1-76) UBC(381-456) GPIN-CD14(20-345) K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1TLR4 K63polyUb-TRAF3 TRAF3 TAB3 LY96 TICAM1 UBC(457-532) LPS GPIN-CD14(20-345) p-T184,T187-MAP3K7 Regulated NecrosisTRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14phosphorylated IRF3and/or IRF7 dimerCHUK LPS TAB3 UBB(1-76) UBB(153-228) UBC(153-228) LPS IKK related kinasesTBK1/IKK epsilonUBC(381-456) p-S172-IKBKE activatedTLR4:TICAM1:K63pUb-TRAF6:free K63pUb:activated TAK1 complexUBC(305-380) p-4S,T404-IRF3,p-S477,S479-IRF7MAP3K7 UBC(305-380) IRF3,IRF7UBC(229-304) p-S172-TBK1 GPIN-CD14(20-345) GPIN-CD14(20-345) UBC(153-228) TLR4 RPS27A(1-76) IKBKE LY96 LY96 UBC(609-684) K63polyUb-TRAF3 LY96 TLR4 activatedTLR4:TICAM1:K63pUb-TRAF6:free K63pUb:TAK1complexGPIN-CD14(20-345) p-S477,S479-IRF7 BIRC3 K63polyUb-TRAF3 K63polyUb-RIPK1 LPS TICAM1 UBC(1-76) active caspase-8IRF3 ATPUBC(533-608) TAB1:TAB2,TAB3:TAK1activatedTLR4:TRIF:RIP1:FADD:pro-caspase-8p-4S,T404-IRF3 TLR4 TAB2 TICAM1 UBB(1-76) LPS UBC(305-380) GPIN-CD14(20-345) TLR4 p-T184,T187-MAP3K7 LPS LPS MyrG-p-S16-TICAM2 TAB1 K63pUb-TANK:K63pUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14MyrG-p-S16-TICAM2 TICAM1 UBB(1-76) TLR4 TAK1 activates NFkBby phosphorylationand activation ofIKKs complexCHUK RPS27A(1-76) GPIN-CD14(20-345) TICAM1 GPIN-CD14(20-345) K63polyUb SARM-1 UBB(77-152) LY96 IRF7 UBC(229-304) LY96 TANK UbATPLY96 TICAM1 LY96 UBC(305-380) LPS UBC(1-76) ATPUBB(77-152) LY96 UBE2D2 TBK1 LY96 MyrG-p-S16-TICAM2 TANK:K63-poly-Ub-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14UBC(229-304) UBC(381-456) K63polyUbactivatedTLR4:TRIF:RIP1:FADDLPS GPIN-CD14(20-345) ADPIKBKG LY96 K63polyUb-TRAF6 RIPK1 K63polyUb UBC(77-152) TRAF3TICAM1 UBB(77-152) MyrG-p-S16-TICAM2 UBC(77-152) UBC(533-608) SARM-1GPIN-CD14(20-345) HBV dsRNA intermediate form TLR4 UBC(609-684) p-IRAK2 IKBKG TICAM1 p-4S,T404-IRF3 TLR4 TLR3 FADDTICAM1 activatedTLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiGPIN-CD14(20-345) K63polyUb-TANK K63polyUb-TRAF6 UBA52(1-76) TAB3 UBC(609-684) MyrG-p-S16-TICAM2 TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14GPIN-CD14(20-345) LPS UBC(153-228) UBB(153-228) CASP8(1-479) K63polyUbMyrG-p-S16-TICAM2 LY96 TANKMyrG-p-S16-TICAM2 K63polyUb-RIPK1 SARM:TICAM1:TRAM:TLR4:LY96:LPS:CD14UBC(153-228) RPS27A(1-76) UbApoptosisMAP kinaseactivationTLR4 MyrG-p-S16-TICAM2 UBC(77-152) UBC(1-76) UBC(533-608) LY96 UBB(153-228) K63polyUb-TRAF6 UBC(457-532) TLR4 TLR4 LY96 TLR4 Influenza A dsRNA intermediate form K63pUb-RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14UBE2V1 LY96 UBC(77-152) UBE2D1 K63polyUb-TRAF3 MyrG-p-S16-TICAM2 TLR4 TICAM1 BIRC2 TICAM1 LPS MyrG-p-S16-TICAM2 K63polyUb-TRAF6 GPIN-CD14(20-345) GPIN-CD14(20-345) RIPK3TLR4 K63polyUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14TRIF:activated TLR4UBA52(1-76) TAB2 UBB(1-76) MyrG-p-S16-TICAM2 LPS TAB1 GPIN-CD14(20-345) K63polyUb-TANK IKBKB TAB1 MyrG-p-S16-TICAM2 K63polyUb-TANK RIPK1 MyrG-p-S16-TICAM2 LPS LY96 K63polyUb LY96 RIPK3 RIPK1 MyrG-p-S16-TICAM2 RIPK1 CHUK:IKBKB:IKBKGUBC(457-532) GPIN-CD14(20-345) TLR4 ADPMAP3K7 TICAM1 LY96 MyrG-p-S16-TICAM2 LPS LPS IKBKB RPS27A(1-76) TRAM:TLR4:LY96:LPS:CD14MyrG-p-S16-TICAM2 MyrG-p-S16-TICAM2 TICAM1 TICAM1 TAB3 GPIN-CD14(20-345) Rotavirus dsRNA GPIN-CD14(20-345) PTPN11MyrG-p-S16-TICAM2 UBC(1-76) RIPK1 IRF3 K63polyUb-TRAF6 CASP8(217-374) UBC(229-304) p-S477,S479-IRF7 p-S172-IKBKE 265, 15, 6111, 4117, 5318, 22267, 16, 57, 639, 31, 41395628, 6115, 61565617, 53562, 13, 32, 40, 43...561511, 319, 15, 27, 53, 6163920, 21, 7344414, 654115, 613915, 28, 615651, 7433, 37, 52


MyD88-independent signaling pathway is shared by TLR3 and TLR4 cascades. TIR-domain-containing adapter-inducing interferon-beta (TRIF or TICAM1) is a key adapter molecule in transducing signals from TLR3 and TLR4 in a MyD88-independent manner (Yamamoto M et al. 2003a). TRIF is recruited to ligand-stimulated TLR3 or 4 complex via its TIR domain. TLR3 directly binds TRIF (Oshiumi H et al 2003). In contrast, TLR4-mediated signaling pathway requires two adapter molecules, TRAM (TRIF-related adapter molecule or TICAM2) and TRIF. TRAM(TICAM2) is thought to bridge between the activated TLR4 complex and TRIF (Yamamoto M et al. 2003b, Tanimura N et al. 2008, Kagan LC et al. 2008).

TRIF recruitment to TLR complex stimulates distinct pathways leading to production of type 1 interferons (IFNs), pro-inflammatory cytokines and induction of programmed cell death. View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 166166
Reactome version: 66
Reactome Author 
Reactome Author: de Bono, Bernard

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  1. 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
  2. Ashkenazi A.; ''Targeting death and decoy receptors of the tumour-necrosis factor superfamily.''; PubMed Europe PMC
  3. 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
  4. Fitzgerald KA, Rowe DC, Golenbock DT.; ''Endotoxin recognition and signal transduction by the TLR4/MD2-complex.''; PubMed Europe PMC
  5. 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
  6. 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
  7. Bardwell AJ, Frankson E, Bardwell L.; ''Selectivity of docking sites in MAPK kinases.''; PubMed Europe PMC
  8. 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
  9. 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
  10. Gangloff M, Gay NJ.; ''MD-2: the Toll 'gatekeeper' in endotoxin signalling.''; PubMed Europe PMC
  11. 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
  12. 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
  13. Cory S, Huang DC, Adams JM.; ''The Bcl-2 family: roles in cell survival and oncogenesis.''; PubMed Europe PMC
  14. 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
  15. 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
  16. Dong C, Davis RJ, Flavell RA.; ''MAP kinases in the immune response.''; PubMed Europe PMC
  17. 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
  18. 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
  19. Keller N, Mares J, Zerbe O, Grütter MG.; ''Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation.''; PubMed Europe PMC
  20. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S.; ''TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway.''; PubMed Europe PMC
  31. Piao W, Song C, Chen H, Diaz MA, Wahl LM, Fitzgerald KA, Li L, Medvedev AE.; ''Endotoxin tolerance dysregulates MyD88- and Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling.''; PubMed Europe PMC
  32. Kerr JF.; ''History of the events leading to the formulation of the apoptosis concept.''; PubMed Europe PMC
  33. 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
  34. 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
  35. Panne D, McWhirter SM, Maniatis T, Harrison SC.; ''Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch.''; PubMed Europe PMC
  36. 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
  37. Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N.; ''Crosstalk between apoptosis, necrosis and autophagy.''; PubMed Europe PMC
  38. 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
  39. 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
  40. MacFarlane M, Williams AC.; ''Apoptosis and disease: a life or death decision.''; PubMed Europe PMC
  41. 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
  42. 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
  43. Kerr JF, Wyllie AH, Currie AR.; ''Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.''; PubMed Europe PMC
  44. 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
  45. 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
  46. Arch RH, Gedrich RW, Thompson CB.; ''Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death.''; PubMed Europe PMC
  47. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC
  48. 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
  49. Adams JM.; ''Ways of dying: multiple pathways to apoptosis.''; PubMed Europe PMC
  50. 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
  51. 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
  52. 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
  53. 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
  54. 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
  55. 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
  56. 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
  57. Banerjee A, Gerondakis S.; ''Coordinating TLR-activated signaling pathways in cells of the immune system.''; PubMed Europe PMC
  58. 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
  59. Creagh EM, Conroy H, Martin SJ.; ''Caspase-activation pathways in apoptosis and immunity.''; PubMed Europe PMC
  60. Donepudi M, Mac Sweeney A, Briand C, Grütter MG.; ''Insights into the regulatory mechanism for caspase-8 activation.''; PubMed Europe PMC
  61. 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
  62. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K.; ''TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.''; PubMed Europe PMC
  63. Chang L, Karin M.; ''Mammalian MAP kinase signalling cascades.''; PubMed Europe PMC
  64. 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
  65. Núñez Miguel R, Wong J, Westoll JF, Brooks HJ, O'Neill LA, Gay NJ, Bryant CE, Monie TP.; ''A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.''; PubMed Europe PMC
  66. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed Europe PMC
  67. 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
  68. 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
  69. 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
  70. Cory S, Adams JM.; ''The Bcl2 family: regulators of the cellular life-or-death switch.''; PubMed Europe PMC
  71. 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
  72. 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
  73. 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
  74. 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


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101287view11:17, 1 November 2018ReactomeTeamreactome version 66
100824view20:48, 31 October 2018ReactomeTeamreactome version 65
100365view19:23, 31 October 2018ReactomeTeamreactome version 64
99911view16:06, 31 October 2018ReactomeTeamreactome version 63
99467view14:39, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99122view12:40, 31 October 2018ReactomeTeamreactome version 62
94000view13:50, 16 August 2017ReactomeTeamreactome version 61
93610view11:28, 9 August 2017ReactomeTeamreactome version 61
88020view13:30, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86718view09:24, 11 July 2016ReactomeTeamreactome version 56
83098view09:58, 18 November 2015ReactomeTeamVersion54
81768view10:14, 26 August 2015ReactomeTeamVersion53
76995view08:28, 17 July 2014ReactomeTeamFixed remaining interactions
76700view12:06, 16 July 2014ReactomeTeamFixed remaining interactions
76026view10:08, 11 June 2014ReactomeTeamRe-fixing comment source
75735view11:21, 10 June 2014ReactomeTeamReactome 48 Update
75085view14:04, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74732view08:48, 30 April 2014ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (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:IKBKG:K63pUb-RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-937030 (Reactome)
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)
GPIN-CD14(20-345) ProteinP08571 (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)
K63-linked polyUb TRAF6 complexesComplexR-HSA-975153 (Reactome)
K63-pUb-TRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-936965 (Reactome)
K63pUb-RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-937016 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-5362507 (Reactome)
K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1ComplexR-HSA-847073 (Reactome)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb-RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
K63polyUb-TANK ProteinQ92844 (Uniprot-TrEMBL)
K63polyUb-TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
K63polyUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-2213008 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LPS MetaboliteCHEBI:16412 (ChEBI)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
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)
MyrG-p-S16-TICAM2 ProteinQ86XR7 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
RIP1 ubiqutin ligasesComplexR-HSA-2569050 (Reactome)
RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-168912 (Reactome)
RIP3:TICAM1:activated TLR4ComplexR-HSA-2569055 (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). 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. 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:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-2559578 (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:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-5362479 (Reactome)
TANKProteinQ92844 (Uniprot-TrEMBL)
TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-166172 (Reactome)
TICAM1ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-2201339 (Reactome)
TRAF3ProteinQ13114 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-936976 (Reactome)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-166163 (Reactome)
TRIF:activated TLR4ComplexR-HSA-2569052 (Reactome)
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 TLR4:TICAM1:K63pUb-TRAF6:free K63pUb:TAK1complexComplexR-HSA-936954 (Reactome)
activated TLR4:TICAM1:K63pUb-TRAF6:free K63pUb:activated TAK1 complexComplexR-HSA-936946 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7ComplexR-HSA-937070 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiComplexR-HSA-936970 (Reactome)
activated TLR4:TRIF:RIP1:FADD:pro-caspase-8ComplexR-HSA-2562542 (Reactome)
activated TLR4:TRIF:RIP1:FADDComplexR-HSA-2562577 (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-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
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)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-166245 (Reactome)
ADPArrowR-HSA-936941 (Reactome)
ADPArrowR-HSA-936951 (Reactome)
ATPR-HSA-166245 (Reactome)
ATPR-HSA-936941 (Reactome)
ATPR-HSA-936951 (Reactome)
CASP8(1-479)R-HSA-2562541 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-937029 (Reactome)
FADDR-HSA-2562541 (Reactome)
IKK related kinases TBK1/IKK epsilonR-HSA-936941 (Reactome)
IRF3,IRF7R-HSA-166271 (Reactome)
K63-linked polyUb TRAF6 complexesmim-catalysisR-HSA-450358 (Reactome)
K63-pUb-TRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-936952 (Reactome)
K63-pUb-TRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-936947 (Reactome)
K63pUb-RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-168915 (Reactome)
K63pUb-RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-937029 (Reactome)
K63pUb-RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14TBarR-HSA-2562541 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-5362500 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-936941 (Reactome)
K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1ArrowR-HSA-937075 (Reactome)
K63polyUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-2213017 (Reactome)
K63polyUb-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-5362486 (Reactome)
K63polyUbArrowR-HSA-450358 (Reactome)
K63polyUbR-HSA-168915 (Reactome)
K63polyUbR-HSA-936947 (Reactome)
PTPN11TBarR-HSA-166271 (Reactome)
R-HSA-166175 (Reactome) TRIF (TICAM1) mediates the MyD88-independent pathway from TLR4.
R-HSA-166245 (Reactome) Human IRF-3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKK-i. 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 IRF-3 dimerization.

IRF-3 and IRF-7 transcription factors possess distinct structural characteristics; IRF-7 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-166271 (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-168915 (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-168921 (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-2201338 (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-2213017 (Reactome) TRIF 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-2559568 (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).

LPS treatment led to a rapid increase of the SARM expression in peripheral blood mononuclear cells (PBMCs) and as a result an increased association between SARM and TICAM1 (Carty M et al. 2006). Moreover, suppression of endogenous SARM expression by siRNA led to enhanced TLR4-dependent gene induction in both transformed HEK293 and primary PBMC cells, while endotoxin-tolerant human monocytes showed increased expression of SARM and decreased activation of TICAM1-dependent cytokines (Carty M et al. 2006; Piao W et al. 2009). Thus, SARM negatively regulates TICAM1 (TRIF)-dependent TLR4 signaling pathway.

R-HSA-2562541 (Reactome) TRIF 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-2562564 (Reactome) TLR4 and TLR3 signaling pathways 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-2569057 (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-450358 (Reactome) Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) 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.
R-HSA-5362486 (Reactome) TRAF family member-associated NF-kB 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-5362500 (Reactome) Upon stimulation by pathogen-associated inflammatory signals TANK associates with TRAF3 which results 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-936941 (Reactome) Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and inhibitor of ?B kinase epsilon (IKKi) induce type I interferon expression and modulate nuclear factor ?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-936947 (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.
R-HSA-936951 (Reactome) The 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-936952 (Reactome) TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. 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-936985 (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-937029 (Reactome) Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation.
R-HSA-937075 (Reactome) Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol
RIP1 ubiqutin ligasesmim-catalysisR-HSA-168915 (Reactome)
RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-168921 (Reactome)
RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-168915 (Reactome)
RIP1:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-2562541 (Reactome)
RIP3:TICAM1:activated TLR4ArrowR-HSA-2569057 (Reactome)
RIPK1R-HSA-168921 (Reactome)
RIPK3R-HSA-2569057 (Reactome)
RIPK3TBarR-HSA-168921 (Reactome)
SARM-1R-HSA-2559568 (Reactome)
SARM:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-2559568 (Reactome)
SARM:TICAM1:TRAM:TLR4:LY96:LPS:CD14TBarR-HSA-168921 (Reactome)
SARM:TICAM1:TRAM:TLR4:LY96:LPS:CD14TBarR-HSA-2201338 (Reactome)
SARM:TICAM1:TRAM:TLR4:LY96:LPS:CD14TBarR-HSA-936985 (Reactome)
TAB1:TAB2,TAB3:TAK1R-HSA-936947 (Reactome)
TANK:K63-poly-Ub-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-5362486 (Reactome)
TANK:K63-poly-Ub-TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-5362500 (Reactome)
TANKR-HSA-5362486 (Reactome)
TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-166175 (Reactome)
TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-937075 (Reactome)
TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-168921 (Reactome)
TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-2201338 (Reactome)
TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-2559568 (Reactome)
TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-936985 (Reactome)
TICAM1R-HSA-166175 (Reactome)
TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-2201338 (Reactome)
TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-2213017 (Reactome)
TRAF3:TICAM1:TRAM:TLR4:LY96:LPS:CD14mim-catalysisR-HSA-2213017 (Reactome)
TRAF3R-HSA-2201338 (Reactome)
TRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-936985 (Reactome)
TRAF6:TICAM1:TRAM:TLR4:LY96:LPS:CD14R-HSA-936952 (Reactome)
TRAF6R-HSA-936985 (Reactome)
TRAM:TLR4:LY96:LPS:CD14R-HSA-166175 (Reactome)
TRIF:activated TLR4R-HSA-2569057 (Reactome)
UbR-HSA-2213017 (Reactome)
UbR-HSA-450358 (Reactome)
UbR-HSA-5362500 (Reactome)
UbR-HSA-936952 (Reactome)
activated TLR4:TICAM1:K63pUb-TRAF6:free K63pUb:TAK1complexArrowR-HSA-936947 (Reactome)
activated TLR4:TICAM1:K63pUb-TRAF6:free K63pUb:TAK1complexR-HSA-936951 (Reactome)
activated TLR4:TICAM1:K63pUb-TRAF6:free K63pUb:TAK1complexmim-catalysisR-HSA-936951 (Reactome)
activated TLR4:TICAM1:K63pUb-TRAF6:free K63pUb:activated TAK1 complexArrowR-HSA-936951 (Reactome)
activated TLR4:TICAM1:K63pUb-TRAF6:free K63pUb:activated TAK1 complexR-HSA-937075 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7ArrowR-HSA-166271 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7R-HSA-166245 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7mim-catalysisR-HSA-166245 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiArrowR-HSA-166245 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiArrowR-HSA-936941 (Reactome)
activated TLR4:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiR-HSA-166271 (Reactome)
activated TLR4:TRIF:RIP1:FADD:pro-caspase-8ArrowR-HSA-2562541 (Reactome)
activated TLR4:TRIF:RIP1:FADD:pro-caspase-8R-HSA-2562564 (Reactome)
activated TLR4:TRIF:RIP1:FADD:pro-caspase-8mim-catalysisR-HSA-2562564 (Reactome)
activated TLR4:TRIF:RIP1:FADDArrowR-HSA-2562564 (Reactome)
active caspase-8ArrowR-HSA-2562564 (Reactome)
p-4S,T404-IRF3,p-S477,S479-IRF7ArrowR-HSA-166245 (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)

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