DDX58/IFIH1-mediated induction of interferon-alpha/beta (Homo sapiens)

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2, 10, 23, 47, 63...8, 9, 26, 5814, 15426620, 2411, 593866554824, 32, 4329, 31, 44, 54, 56...16, 28, 7011, 596, 34, 39, 505, 62, 71494829, 31, 44, 54, 67486157, 60224, 40, 733024, 70645, 1741, 51, 52, 70193, 37, 467, 35, 534169213, 37, 4629, 31, 44, 54, 6733, 645313, 18, 5712, 24, 3645, 731, 28, 35, 55, 72dsRNARIG-I/MDA5IPS-1 dsRNARIG-1/MDA5IPS-1Ub-TRAF3 dsRNARIG-I/MDA5 RIG-I E3 ubiquitin ligases IKK related kinases TBK1/IKK epsilon dsRNARIG-I/MDA5 FADDCasp-8/10 prodomain dsRNARIG-I/MDA5 p-IRF3p-IRF3 dsRNAUb-RIG-ITRIM25 dsRNAMDA5 dsRNAUb-RIG-ITRIM25 dsRNARIG-I/MDA5IPS-1 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6 dsRNAMDA5 RIG-I E3 ubiquitin ligases RIG-I E3 ubiquitin ligases TRAF2 and TRAF6 dsRNAUb-RIG-ITRIM25 AGE adducts dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANKTBK1/IKKi dsRNAMDA5 dsRNAUb-RIG-ITRIM25 IPS-1RIP-1/FADDprocaspase-8/10 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANKTBK1/IKKi TAX1BP1TNFAIP3 ISG15RIG-I conjugate RIG-I E3 ubiquitin ligases dsRNARIG-1/MDA5IPS-1Ub-TRAF3TBK1/IKKi ISGylated IRF3 CBP/p300 dsRNAMDA5 FADDprocaspase-8/10 dimer p-2S-IRF7p-2S-IRF7 dsRNAMDA5 dsRNAMDA5 dsRNAMDA5 dsRNAUb-RIG-ITRIM25 RIG-I E3 ubiquitin ligases RIG-I E3 ubiquitin ligases dsRNAUb-RIG-ITRIM25 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANKTBK1/IKKiIRF7 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANK dsRNARIG-I/MDA5NLRC5 p-2S-IRF7p-2S-IRF7 K48polyUb RIG-I/MDA5 dsRNARIG-I/MDA5IPS-1RIP-1/FADDProcasp-8/10 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6MEKK1 RIG-I E3 ubiquitin ligases cytosolPromoter region of type-I IFN genes IKK related kinases TBK1/IKK epsilon CBP/p300 p-IRF3 dimerPIN1 dsRNARIG-I/MDA5IPS-1PCBP2 IRF3-PIRF7-P CBP/p300pIRF7pIRF7 dsRNARIG-I/MDA5 dsRNAUb-RIG-ITRIM25 p-T,4S-IRF3p-T,4S-IRF3 IPS-1RIP-1/FADD dsRNAUb-RIG-ITRIM25 IRF3 bound to IFN-beta promoter dsRNARIG-I/MDA5 Activated IKK Complex dsRNARIG-I/MDA5 VAF dsRNAMDA5 IRF-1IFN-alpha promoter dsRNAUb-RIG-ITRIM25 RIG-I E3 ubiquitin ligases dsRNARIG-1/MDA5IPS-1Ub-TRAF3TBK1/IKKiIRF3/IRF7 ATG5-ATG12 conjugate IPS-1TRAF2/TRAF6 NFkB Complex IPS-1TRAF2/TRAF6 ISG15UBEIL/UbcH8CEB1 Nuclear factor NF-kappa-B dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANK dsRNARIG-I/MDA5IPS-1ATG5-ATG12 dsRNA bound to RIG-I IRF3-PIRF7-P dsRNARIG-I/MDA5IPS-1 IPS-1TRAF2/TRAF6 dsRNARIG-I/MDA5 dsRNAMDA5 dsRNARIG-I/MDA5IPS-1RIP-1/FADD procaspase-8/10 dsRNAUb-RIG-ITRIM25 dsRNAMDA5 IPS-1ATG5-ATG12 conjugate dsRNAUb-RIG-ITRIM25 dsRNARIG-I/MDA5 dsRNARIG-I/MDA5K48 Ub-IPS-1 RIG-I E3 ubiquitin ligases dsRNAMDA5 p-2S-IRF7p-2S-IRF7 IRF1Promotors of IFN alpha, IFN beta CBP/p300pIRF7pIRF7 dsRNAUb-RIG-ITRIM25 p-2S-IRF7p-2S-IRF7 dsRNARIG-I/MDA5TRAF2/TRAF6IPS-1RIP-1/FADDCasp-8/10 prodomain NFkB Complex dsRNARIG-I/MDA5IPS-1 dsRNAMDA5 dsRNARIG-I/MDA5 dsRNAMDA5 dsRNARIG-I/MDA5 IRF1Promoter region of IFN beta ATG5-ATG12 conjugate IPS-1ATG5-ATG12 conjugate Casp-8/10 prodomain dsRNAMDA5 RIG-I E3 ubiquitin ligases NF-kappaB inhibitor dsRNARIG-I/MDA5 dsRNAMDA5 NFkB Complex AGE adductsPeptide E2 enzymes UbcH8/UBE1L TBK1/IKKiSIKE1 CBP/p300 RIG-I E3 ubiquitin ligases IRF3-PIRF7-P IRF3-P dimerCBP/p300 IkBsNFkB VAF dsRNARIG-I/MDA5IPS-1 dsRNARIG-1/MDA5IPS-1TRAF3 RIG-I E3 ubiquitin ligases AGER ligands procaspase-8/10 IKKAIKKBNEMO TRAF2 and TRAF6 dsRNAUb-RIG-ITRIM25 RIG-I E3 ubiquitin ligases MDA5DAK IPS-1RIP-1/FADDprocaspase-8/10 dimer VAF IKKAIKKBNEMO mitochondriondsRNAUb-RIG-ITRIM25 RIG-I E3 ubiquitin ligases Nuclear factor NF-kappa-B p-T,4S-IRF3p-T,4S-IRF3 dsRNAMDA5 dsRNAUb-RIG-ITRIM25 TRAF2 and TRAF6 TRAF2 and TRAF6 IRF3/ IRF7 dsRNARIG-1/MDA5IPS-1Ub-TRAF3 p-2S-IRF7p-2S-IRF7 dsRNARIG-I/MDA5 RIG-I E3 ubiquitin ligases IRF2promoters of INF alpha, INF beta dsRNAUb-RIG-ITRIM25 AGER ligandsAGER RIG-I E3 ubiquitin ligases IKK related kinases TBK1/IKK epsilon dsRNARIG-I/MDA5 RIG-I E3 ubiquitin ligases dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6 RIG-I E3 ubiquitin ligases RIG-I E3 ubiquitin ligases procaspase-8/10 dimer dsRNAMDA5 Casp-8/10 prodomain FADDprocaspase-8/10 RNF125E2 enzyme dsRNAUb-RIG-ITRIM25 dsRNAUb-RIG-ITRIM25 IRF3-PIRF7-P S100A12 dimer dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANK dsRNARIG-I/MDA5 IKKAIKKBNEMO VAF/pIRF7CBP/p300 p-IRF3p-IRF3 IRF3-PIRF7-P S100B homodimer dsRNARIG-I/MDA5IPS-1 CBP/p300 ISG15UBEIL/UbcH8CEB1 p-T,4S-IRF3p-T,4S-IRF3 VAF/pIRF7CBP/p300 dsRNAUb-RIG-ITRIM25 TAX1BP1TNFAIP3 dsRNAUb-RIG-ITRIM25 IRF2Promoter region of INF alpha IPS-1TRAF2/TRAF6 dsRNARIG-I/MDA5 IKK related kinases TBK1/IKK epsilon IPS-1RIP-1/FADDCasp-8/10 prodomain CBP/p300 dsRNARIG-I/MDA5IPS-1RIP-1/FADDprocaspase-8/10 dimer p-T,4S-IRF3p-T,4S-IRF3 dsRNARIG-1/MDA5IPS-1Ub-TRAF3TBK1/IKKi dsRNARIG-I/MDA5TRAF2/TRAF6IPS-1RIP-1/FADDCasp-8/10 prodomain dsRNARIG-I/MDA5TRAF2/TRAF6IPS-1RIP-1/FADDCasp-8/10 prodomainIKK complex IPS-1RIP-1/FADDCasp-8/10 prodomain dsRNARIG-I/MDA5 E2 enzymes UbcH8/UBE1L dsRNARIG-I/MDA5 VAF/pIRF7CBP/p300 bound to type I IFN gene promoter dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6 IPS-1NLRX1 dsRNAMDA5 TRAF2 and TRAF6 dsRNAMDA5 TAX1BP1TNFAIP3TBK1/IKKi FADDCasp-8/10 prodomain Nuclear factor NF-kappa-B RIG-I E3 ubiquitin ligases CBP/p300pIRF7pIRF7 nucleoplasmdsRNARIG-I/MDA5 dsRNAMDA5 dsRNAMDA5 IKK related kinases TBK1/IKK epsilon dsRNAUb-RIG-ITRIM25 IRF3-P dimerCBP/p300 CBP/p300 dsRNARIG-I/MDA5 dsRNARIG-1/MDA5IPS-1Ub-TRAF3 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6 IKK related kinases TBK1/IKK epsilon dsRNARIG-I/MDA5K48 Ub-IPS-1PCBP2AIP4 RIG-I E3 ubiquitin ligases IPS-1TRAF2/TRAF6 dsRNARIG-I/MDA5 IRF2Promoter region of INF beta Promotor region of interferon betap-S477,S479-IRF7 p-S477,S479-IRF7VAF IFIH1 IKBKE p-4S,T404-IRF3 p-S477,S479-IRF7 TRIM25 MAVS MAVS RNF135 dsRNA bound to RIG-IIFIH1 K63polyUb-DDX58 APPMAVS CASP10K63polyUb-TRAF3 DDX58K63polyUb-TRAF3 NLRC5DDX58 IRF1 IRF7 TBK1 DAKIKBKE K63polyUb-DDX58 dsRNARIG-I/MDA5IPS-1RIP-1/FADDFADD p-4S,T404-IRF3 ATP IKBKG IFIH1 K63polyUb-TRAF3CREBBPMAVSIKBKG dsRNAMDA5CREBBPTANKprocaspase-8/10NLRC5 RNF135 CASP8p-4S,T404-IRF3 RNF135 TRAF3 ATG12 TAX1BP1TNFAIP3MAVS CREBBPRNF135 RIPK1 TRIM25 K63polyUb-DDX58 AGER RIPK1 K63polyUb-DDX58 TRIM25 RNF135 dsRNARIG-I/MDA5IPS-1RIP-1/FADDProcasp-8/10p-S477,S479-IRF7 TANK IPS-1ATG5-ATG12 conjugateK48polyUb RIG-I/MDA5K63polyUb-DDX58 UBE2L6 TRAF2 IFIH1 p-S177,S181-IKBKB IRF3 bound to IFN-beta promoterATP TRAF6 TBK1 TBK1 K63polyUb-DDX58 FADD SIKE1 FADD IFIH1 IFIH1 MAVS ATP PCBP2 TRIM25 NFKB1ISG15 p-2S-IRF7p-2S-IRF7dsRNARIG-I/MDA5IPS-1dsRNAUb-RIG-ITRIM25NLRX1 APPK63polyUb-DDX58 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANKTRIM25 K48polyUb-DDX58 SAA1K63polyUb-DDX58 IRF3 E2 enzyme MAVS TRAF6 ATPTRIM25 ATP TRIM25 ATP RNF135 HERC5 K63polyUb-DDX58 MAVS ADPEP300K48polyUb-TRAF3CREBBPMAVS TRIM25 K48polyUb-MAVS MAVS IFIH1 IKBKG MDA5DAKCASP10IFIH1 IRF3/ IRF7ATPCHUK CASP8IKBKB MAVS IRF2promoters of INF alpha, INF betaK63polyUb-TRAF3 RNF135 RNF135 K63-UbK63polyUb-DDX58 IKBKE RIPK1 NFKBIA ADPATP VAF/pIRF7CBP/p300 bound to type I IFN gene promoterp-IRF3 dimerPIN1RNF135 K63polyUb-DDX58CASP8TRAF2 and TRAF6ATP Activated IKK ComplexMAVS IFIH1 p-4S,T404-IRF3 K63polyUb-DDX58 ATP K63polyUb-DDX58 dsRNARIG-1/MDA5IPS-1Ub-TRAF3TBK1/IKKiIRF3/IRF7ISG15 p-S477,S479-IRF7 p-4S,T404-IRF3 p-S477,S479-IRF7 MAVS OTUD5TRAF2 TBK1 RELA ADPFADDTANK HERC5 ATP p-T,4S-IRF3p-T,4S-IRF3RNF135 ATP K63polyUb-DDX58 ATP p-5S,T404-IRF3 ISG15UBEIL/UbcH8CEB1TAX1BP1 ADPIFIH1 CREBBPATP p-2S-IRF7p-2S-IRF7TRIM25 ATP dsRNARIG-I/MDA5IPS-1RIP-1/FADDprocaspase-8/10 dimerIkBsNFkBIKKAIKKBNEMOCASP8CASP8Promoter region of type-I IFN genesATP EP300CASP8MAVS HMGB1 K63polyUb-DDX58 MAP3K1TRIM25 ATG5 K63polyUb-TRAF3 IFIH1 NLRX1NFkB ComplexIRF7 UBE2L6 MAP3K1IFIH1 ATG12 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6K63polyUb-DDX58 EP300CASP10CBP/p300pIRF7pIRF7CHUK p-5S,T404-IRF3 K63polyUb-DDX58 ITCHCASP10RNF135 RNF125CREBBPTNFAIP3ATPNFKB1p-S477,S479-IRF7 MAVS RIPK1IKBKE ATP p-4S,T404-IRF3 RIPK1 p-T,4S-IRF3p-T,4S-IRF3IFNB1TRAF2 RELA DAK ATPTAX1BP1TNFAIP3TBK1/IKKiNFkB ComplexIRF7p-IRF3p-IRF3PCBP2ATP RNF135 TRAF2 IFIH1 K48polyUb-TRAF3 K48polyUb-IFIH1 IKBKB K63polyUbIKBKG FADD IFIH1 IRF3-PIRF7-PTRIM25 IFIH1 p-S477,S479-IRF7 dsRNARIG-I/MDA5K48 Ub-IPS-1PCBP2AIP4NFKBIB TRIM25 NFKB1TRIM25 ISG15RIG-I conjugateK63polyUb-DDX58 ATG5 dsRNARIG-I/MDA5NLRC5ISGylated IRF3Phospho-NF-kappaB InhibitorISG15 TRAF6 IFIH1 RNF135 NFKB2RIPK1 MAVS IFIH1 p-S176,S180-CHUK TBK1 Viral dsRNA S100A12 MAVS dsRNARIG-1/MDA5IPS-1TRAF3RNF135 RELA RIG-I E3 ubiquitin ligasesIFIH1 NFKB2MAVS NFKB2p-S477,S479-IRF7 dsRNARIG-1/MDA5IPS-1Ub-TRAF3TBK1/IKKiIKBKB TNFAIP3TRIM25 TRIM25 K63polyUb-DDX58 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANKTBK1/IKKiIFIH1 VAF/pIRF7CBP/p300N-epsilon-CASP8IKBKE IRF2 IFIH1 CBP/p300RNF125E2 enzyme TRIM25 TRIM25 TBK1 CHUK S100B NECML TRIM25 ATP ATP Peptide EP300dsRNARIG-I/MDA5IPS-1PCBP2dsRNARIG-I/MDA5IPS-1ATG5-ATG12dsRNARIG-1/MDA5IPS-1Ub-TRAF3IRF3-PIRF7-PRNF135 ATP IFN alpha/beta RNF135 FADD PIN1 TRIM25 RNF135 DDX58 UBA7 EP300ATP IKBKE SIKE1TANK MAVS IFIH1 K63polyUb-DDX58 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6MEKK1phosphorylated IRF3/IRF7CASP10CASP10dsRNARIG-I/MDA5IKKAIKKBNEMOIPS-1NLRX1UBA7 TBK1/IKKiSIKE1p-4S,T404-IRF3 RNF135 ATPMAVS TAX1BP1 UbK63polyUb-DDX58 AGER ligandsAGERIFIH1 IKK related kinases TBK1/IKK epsilonTRAF2 dsRNARIG-I/MDA5IPS-1TRAF2/TRAF6TANKTBK1/IKKiIRF7K63polyUb-DDX58 ATP CYLDITCH PCBP2 DHX58DDX58/IFIH1p-4S,T404-IRF3 TRIM25 K63polyUb-DDX58 RNF135 IRF3 RNF135 EP300K48polyUbdsRNARIG-I/MDA5TRAF2/TRAF6IPS-1RIP-1/FADDCasp-8/10 prodomainIKK complexp-4S,T404-IRF3 dsRNARIG-I/MDA5TRAF2/TRAF6IPS-1RIP-1/FADDCasp-8/10 prodomainIRF1Promotors of IFN alpha, IFN betaPIN1ATP K48polyUb-RNF125 IRF3-P dimerCBP/p300TRAF6 TRAF6 TRIM25 RNF135 34, 45, 5034, 45, 5034, 45, 5034, 45, 5034, 45, 506834, 45, 50272734, 45, 5034, 45, 506834, 45, 5034, 45, 5045452734, 45, 504934, 45, 5027274934, 45, 504534, 45, 5025, 742734, 45, 5034, 45, 5034, 45, 5034, 45, 506834, 45, 5034, 45, 5034, 45, 50596634, 45, 5034, 45, 50


Description

RIG-I-like helicases (RLHs) the retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) are RNA helicases that recognize viral RNA present within the cytoplasm. Functionally RIG-I and MDA5 positively regulate the IFN genes in a similar fashion, however they differ in their response to different viral species. RIG-I is essential for detecting influenza virus, Sendai virus, VSV and Japanese encephalitis virus (JEV), whereas MDA5 is essential in sensing encephalomyocarditis virus (EMCV), Mengo virus and Theiler's virus, all of which belong to the picornavirus family. RIG-I and MDA5 signalling results in the activation of IKK epsilon and (TKK binding kinase 1) TBK1, two serine/threonine kinases that phosphorylate interferon regulatory factor 3 and 7 (IRF3 and IRF7). Upon phosphorylation, IRF3 and IRF7 translocate to the nucleus and subsequently induce interferon alpha (IFNA) and interferon beta (IFNB) gene transcription. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=168928

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  46. Kell A, Stoddard M, Li H, Marcotrigiano J, Shaw GM, Gale M.; ''Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length.''; PubMed Europe PMC Scholia
  47. Nyman TA, Tölö H, Parkkinen J, Kalkkinen N.; ''Identification of nine interferon-alpha subtypes produced by Sendai virus-induced human peripheral blood leucocytes.''; PubMed Europe PMC Scholia
  48. Kim MJ, Hwang SY, Imaizumi T, Yoo JY.; ''Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation.''; PubMed Europe PMC Scholia
  49. Saha SK, Pietras EM, He JQ, Kang JR, Liu SY, Oganesyan G, Shahangian A, Zarnegar B, Shiba TL, Wang Y, Cheng G.; ''Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif.''; PubMed Europe PMC Scholia
  50. Chen ZJ.; ''Ubiquitin signalling in the NF-kappaB pathway.''; PubMed Europe PMC Scholia
  51. Nakhaei P, Mesplede T, Solis M, Sun Q, Zhao T, Yang L, Chuang TH, Ware CF, Lin R, Hiscott J.; ''The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation.''; PubMed Europe PMC Scholia
  52. 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
  53. 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
  54. Chen W, Royer WE.; ''Structural insights into interferon regulatory factor activation.''; PubMed Europe PMC Scholia
  55. Li X, Lu C, Stewart M, Xu H, Strong RK, Igumenova T, Li P.; ''Structural basis of double-stranded RNA recognition by the RIG-I like receptor MDA5.''; PubMed Europe PMC Scholia
  56. Potter JA, Randall RE, Taylor GL.; ''Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain.''; PubMed Europe PMC Scholia
  57. 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
  58. Saitoh T, Tun-Kyi A, Ryo A, Yamamoto M, Finn G, Fujita T, Akira S, Yamamoto N, Lu KP, Yamaoka S.; ''Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1.''; PubMed Europe PMC Scholia
  59. Gil J, Alcamí J, Esteban M.; ''Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex.''; PubMed Europe PMC Scholia
  60. Takahashi K, Kawai T, Kumar H, Sato S, Yonehara S, Akira S.; ''Roles of caspase-8 and caspase-10 in innate immune responses to double-stranded RNA.''; PubMed Europe PMC Scholia
  61. Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, Akira S, Gill MA, García-Sastre A, Katze MG, Gale M.; ''Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.''; PubMed Europe PMC Scholia
  62. You F, Sun H, Zhou X, Sun W, Liang S, Zhai Z, Jiang Z.; ''PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4.''; PubMed Europe PMC Scholia
  63. Yang H, Lin CH, Ma G, Baffi MO, Wathelet MG.; ''Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators.''; PubMed Europe PMC Scholia
  64. Sato M, Tanaka N, Hata N, Oda E, Taniguchi T.; ''Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene.''; PubMed Europe PMC Scholia
  65. 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
  66. Kawai T, Akira S.; ''Antiviral signaling through pattern recognition receptors.''; PubMed Europe PMC Scholia
  67. Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L.; ''Activation of the NF-kappaB pathway by caspase 8 and its homologs.''; PubMed Europe PMC Scholia
  68. Mattei F, Schiavoni G, Tough DF.; ''Regulation of immune cell homeostasis by type I interferons.''; PubMed Europe PMC Scholia
  69. Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T.; ''Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300.''; PubMed Europe PMC Scholia
  70. Yazdi S, Naumann M, Stein M.; ''Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB.''; PubMed Europe PMC Scholia
  71. Schnell G, Loo YM, Marcotrigiano J, Gale M.; ''Uridine composition of the poly-U/UC tract of HCV RNA defines non-self recognition by RIG-I.''; PubMed Europe PMC Scholia
  72. Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U.; ''Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases.''; PubMed Europe PMC Scholia
  73. Goutagny N, Severa M, Fitzgerald KA.; ''Pin-ning down immune responses to RNA viruses.''; PubMed Europe PMC Scholia
  74. Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cárdenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM, Xavier R, Ting AT.; ''The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.''; PubMed Europe PMC Scholia
  75. Marié I, Durbin JE, Levy DE.; ''Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7.''; PubMed Europe PMC Scholia
  76. Berghäll H, Sirén J, Sarkar D, Julkunen I, Fisher PB, Vainionpää R, Matikainen S.; ''The interferon-inducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines.''; PubMed Europe PMC Scholia
  77. Lee MK, Kim HE, Park EB, Lee J, Kim KH, Lim K, Yum S, Lee YH, Kang SJ, Lee JH, Choi BS.; ''Structural features of influenza A virus panhandle RNA enabling the activation of RIG-I independently of 5'-triphosphate.''; PubMed Europe PMC Scholia
  78. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC Scholia
  79. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T.; ''The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.''; PubMed Europe PMC Scholia
  80. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S.; ''Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.''; PubMed Europe PMC Scholia
  81. Thomas LR, Stillman DJ, Thorburn A.; ''Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen.''; PubMed Europe PMC Scholia
  82. Marié I, Smith E, Prakash A, Levy DE.; ''Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain.''; PubMed Europe PMC Scholia
  83. Zhang M, Wu X, Lee AJ, Jin W, Chang M, Wright A, Imaizumi T, Sun SC.; ''Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD.''; PubMed Europe PMC Scholia
  84. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S, Jung JU.; ''TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity.''; PubMed Europe PMC Scholia
  85. Lee FS, Hagler J, Chen ZJ, Maniatis T.; ''Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway.''; PubMed Europe PMC Scholia
  86. 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
  87. Honda K, Yanai H, Takaoka A, Taniguchi T.; ''Regulation of the type I IFN induction: a current view.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114870view16:37, 25 January 2021ReactomeTeamReactome version 75
113316view11:38, 2 November 2020ReactomeTeamReactome version 74
112527view15:49, 9 October 2020ReactomeTeamReactome version 73
101439view11:31, 1 November 2018ReactomeTeamreactome version 66
100978view21:09, 31 October 2018ReactomeTeamreactome version 65
100514view19:42, 31 October 2018ReactomeTeamreactome version 64
100060view16:26, 31 October 2018ReactomeTeamreactome version 63
99612view15:00, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94503view09:19, 14 September 2017Mkutmonreactome version 61
86432view09:18, 11 July 2016ReactomeTeamreactome version 56
83061view09:50, 18 November 2015ReactomeTeamVersion54
81373view12:54, 21 August 2015ReactomeTeamVersion53
76841view08:06, 17 July 2014ReactomeTeamFixed remaining interactions
76545view11:53, 16 July 2014ReactomeTeamFixed remaining interactions
75878view09:53, 11 June 2014ReactomeTeamRe-fixing comment source
75578view10:41, 10 June 2014ReactomeTeamReactome 48 Update
74933view13:46, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74577view08:37, 30 April 2014ReactomeTeamReactome46
45045view19:04, 6 October 2011ThomasOntology Term : 'signaling pathway' added !
45044view19:02, 6 October 2011ThomasOntology Term : 'Viral Infection' added !
45043view19:02, 6 October 2011ThomasOntology Term : 'influenza' added !
42120view21:58, 4 March 2011MaintBotAutomatic update
39930view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AGER ProteinQ15109 (Uniprot-TrEMBL)
AGER ligands AGERComplexREACT_24620 (Reactome)
APPProteinP05067 (Uniprot-TrEMBL)
ATG12 ProteinO94817 (Uniprot-TrEMBL)
ATG5 ProteinQ9H1Y0 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated IKK ComplexComplexREACT_7826 (Reactome)
CASP10ProteinQ92851 (Uniprot-TrEMBL)
CASP8ProteinQ14790 (Uniprot-TrEMBL)
CBP/p300

pIRF7

pIRF7
ComplexREACT_25574 (Reactome)
CBP/p300ProteinREACT_25880 (Reactome)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
CYLDProteinQ9NQC7 (Uniprot-TrEMBL)
DAK ProteinQ3LXA3 (Uniprot-TrEMBL)
DAKProteinQ3LXA3 (Uniprot-TrEMBL)
DDX58 ProteinO95786 (Uniprot-TrEMBL)
DDX58/IFIH1ProteinREACT_25428 (Reactome)
DDX58ProteinO95786 (Uniprot-TrEMBL)
DHX58ProteinQ96C10 (Uniprot-TrEMBL)
E2 enzyme ProteinREACT_26340 (Reactome)
EP300ProteinQ09472 (Uniprot-TrEMBL)
FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
HERC5 ProteinQ9UII4 (Uniprot-TrEMBL)
HMGB1 ProteinP09429 (Uniprot-TrEMBL)
IFIH1 ProteinQ9BYX4 (Uniprot-TrEMBL)
IFN alpha/beta ProteinREACT_26595 (Reactome)
IFNB1ProteinP01574 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKE ProteinQ14164 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKK related kinases TBK1/IKK epsilonProteinREACT_21591 (Reactome)
IKKA

IKKB

NEMO
ComplexREACT_7693 (Reactome)
IPS-1 ATG5-ATG12 conjugateComplexREACT_25931 (Reactome)
IPS-1 NLRX1ComplexREACT_26115 (Reactome)
IRF1 Promotors of IFN alpha, IFN betaComplexREACT_26239 (Reactome)
IRF1 ProteinP10914 (Uniprot-TrEMBL)
IRF2 promoters of INF alpha, INF betaComplexREACT_26555 (Reactome)
IRF2 ProteinP14316 (Uniprot-TrEMBL)
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF3 bound to IFN-beta promoterComplexREACT_25617 (Reactome)
IRF3-P IRF7-PComplexREACT_26495 (Reactome)
IRF3-P IRF7-PComplexREACT_26957 (Reactome)
IRF3-P dimer CBP/p300ComplexREACT_26303 (Reactome)
IRF3/ IRF7ProteinREACT_21735 (Reactome)
IRF7 ProteinQ92985 (Uniprot-TrEMBL)
IRF7ProteinQ92985 (Uniprot-TrEMBL)
ISG15 RIG-I conjugateComplexREACT_26209 (Reactome)
ISG15

UBEIL/UbcH8

CEB1
ComplexREACT_26934 (Reactome)
ISG15 ProteinP05161 (Uniprot-TrEMBL)
ISGylated IRF3ComplexREACT_27520 (Reactome)
ITCH ProteinQ96J02 (Uniprot-TrEMBL)
ITCHProteinQ96J02 (Uniprot-TrEMBL)
IkBs NFkBComplexREACT_7272 (Reactome)
K48polyUb RIG-I/MDA5ComplexREACT_25791 (Reactome)
K48polyUb-DDX58 ProteinO95786 (Uniprot-TrEMBL)
K48polyUb-IFIH1 ProteinQ9BYX4 (Uniprot-TrEMBL)
K48polyUb-MAVS ProteinQ7Z434 (Uniprot-TrEMBL)
K48polyUb-RNF125 ProteinQ96EQ8 (Uniprot-TrEMBL)
K48polyUb-TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
K48polyUb-TRAF3ComplexQ13114 (Uniprot-TrEMBL)
K48polyUbREACT_24769 (Reactome)
K63-UbProteinREACT_21627 (Reactome)
K63polyUb-DDX58 ProteinO95786 (Uniprot-TrEMBL)
K63polyUb-DDX58ComplexO95786 (Uniprot-TrEMBL)
K63polyUb-TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
K63polyUb-TRAF3ComplexQ13114 (Uniprot-TrEMBL)
K63polyUbREACT_21645 (Reactome)
MAP3K1ProteinQ13233 (Uniprot-TrEMBL)
MAVS ProteinQ7Z434 (Uniprot-TrEMBL)
MAVSProteinQ7Z434 (Uniprot-TrEMBL)
MDA5 DAKComplexREACT_25465 (Reactome)
N-epsilon-MetaboliteCHEBI:60125 (ChEBI)
NECML MetaboliteCHEBI:53014 (ChEBI)
NFKB1ProteinP19838 (Uniprot-TrEMBL)
NFKB2ProteinQ00653 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
NFkB ComplexComplexREACT_7108 (Reactome)
NFkB ComplexComplexREACT_7143 (Reactome)
NLRC5 ProteinQ86WI3 (Uniprot-TrEMBL)
NLRC5ProteinQ86WI3 (Uniprot-TrEMBL)
NLRX1 ProteinQ86UT6 (Uniprot-TrEMBL)
NLRX1ProteinQ86UT6 (Uniprot-TrEMBL)
OTUD5ProteinQ96G74 (Uniprot-TrEMBL)
PCBP2 ProteinQ15366 (Uniprot-TrEMBL)
PCBP2ProteinQ15366 (Uniprot-TrEMBL)
PIN1 ProteinQ13526 (Uniprot-TrEMBL)
PIN1ProteinQ13526 (Uniprot-TrEMBL)
Peptide MetaboliteCHEBI:16670 (ChEBI)
Phospho-NF-kappaB InhibitorProteinREACT_7645 (Reactome)
Promoter region of type-I IFN genesREACT_25653 (Reactome)
Promotor region of interferon betaREACT_25836 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RIG-I E3 ubiquitin ligasesProteinREACT_25644 (Reactome)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
RNF125 E2 enzyme ComplexREACT_25756 (Reactome)
RNF125ProteinQ96EQ8 (Uniprot-TrEMBL)
RNF135 ProteinQ8IUD6 (Uniprot-TrEMBL)
S100A12 ProteinP80511 (Uniprot-TrEMBL)
S100B ProteinP04271 (Uniprot-TrEMBL)
SAA1ProteinP0DJI8 (Uniprot-TrEMBL)
SIKE1 ProteinQ9BRV8 (Uniprot-TrEMBL)
SIKE1ProteinQ9BRV8 (Uniprot-TrEMBL)
TANK ProteinQ92844 (Uniprot-TrEMBL)
TANKProteinQ92844 (Uniprot-TrEMBL)
TAX1BP1

TNFAIP3

TBK1/IKKi
ComplexREACT_25569 (Reactome)
TAX1BP1 TNFAIP3ComplexREACT_26309 (Reactome)
TAX1BP1 ProteinQ86VP1 (Uniprot-TrEMBL)
TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
TBK1/IKKi SIKE1ComplexREACT_25799 (Reactome)
TNFAIP3ProteinP21580 (Uniprot-TrEMBL)
TRAF2 ProteinQ12933 (Uniprot-TrEMBL)
TRAF2 and TRAF6ProteinREACT_26063 (Reactome)
TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRIM25 ProteinQ14258 (Uniprot-TrEMBL)
UBA7 ProteinP41226 (Uniprot-TrEMBL)
UBE2L6 ProteinO14933 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
VAF ComplexREACT_25426 (Reactome)
VAF/pIRF7 CBP/p300 bound to type I IFN gene promoterComplexREACT_26244 (Reactome)
VAF/pIRF7 CBP/p300ComplexREACT_25775 (Reactome)
Viral dsRNA REACT_6589 (Reactome)
dsRNA MDA5ComplexREACT_26245 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1

TRAF3
ComplexREACT_25597 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1 Ub-TRAF3 TBK1/IKKi

IRF3/IRF7
ComplexREACT_25519 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1 Ub-TRAF3

TBK1/IKKi
ComplexREACT_26022 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1

Ub-TRAF3
ComplexREACT_26564 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

ATG5-ATG12
ComplexREACT_26782 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

PCBP2
ComplexREACT_25961 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 RIP-1/FADD

Procasp-8/10
ComplexREACT_26650 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 RIP-1/FADD

procaspase-8/10 dimer
ComplexREACT_26858 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

RIP-1/FADD
ComplexREACT_26077 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6

MEKK1
ComplexREACT_26122 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK TBK1/IKKi

IRF7
ComplexREACT_26674 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK

TBK1/IKKi
ComplexREACT_25493 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6

TANK
ComplexREACT_27050 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

TRAF2/TRAF6
ComplexREACT_26067 (Reactome)
dsRNA

RIG-I/MDA5

IPS-1
ComplexREACT_26220 (Reactome)
dsRNA

RIG-I/MDA5 K48 Ub-IPS-1 PCBP2

AIP4
ComplexREACT_26024 (Reactome)
dsRNA

RIG-I/MDA5

NLRC5
ComplexREACT_26732 (Reactome)
dsRNA

RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD Casp-8/10 prodomain

IKK complex
ComplexREACT_27017 (Reactome)
dsRNA

RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD

Casp-8/10 prodomain
ComplexREACT_26324 (Reactome)
dsRNA RIG-I/MDA5ComplexREACT_25628 (Reactome)
dsRNA

Ub-RIG-I

TRIM25
ComplexREACT_26009 (Reactome)
dsRNA bound to RIG-IComplexREACT_25966 (Reactome)
p-2S-IRF7 p-2S-IRF7ComplexREACT_21640 (Reactome)
p-2S-IRF7 p-2S-IRF7ComplexREACT_21965 (Reactome)
p-4S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-5S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-IRF3 p-IRF3ComplexREACT_26064 (Reactome)
p-IRF3 dimer PIN1ComplexREACT_26699 (Reactome)
p-S176,S180-CHUK ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S477,S479-IRF7 ProteinQ92985 (Uniprot-TrEMBL)
p-S477,S479-IRF7ProteinQ92985 (Uniprot-TrEMBL)
p-T,4S-IRF3 p-T,4S-IRF3ComplexREACT_7146 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3ComplexREACT_7444 (Reactome)
phosphorylated IRF3/IRF7ProteinREACT_21760 (Reactome)
procaspase-8/10ProteinREACT_26572 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_24935 (Reactome)
ADPArrowREACT_25327 (Reactome)
ADPArrowREACT_25368 (Reactome)
ADPArrowREACT_6848 (Reactome)
AGER ligands AGERArrowREACT_6906 (Reactome)
ATPREACT_24935 (Reactome)
ATPREACT_25327 (Reactome)
ATPREACT_25357 (Reactome)
ATPREACT_25368 (Reactome)
ATPREACT_6848 (Reactome)
Activated IKK ComplexArrowREACT_24935 (Reactome)
Activated IKK Complexmim-catalysisREACT_6848 (Reactome)
CASP10ArrowREACT_24999 (Reactome)
CASP8ArrowREACT_24999 (Reactome)
CBP/p300REACT_25099 (Reactome)
CBP/p300REACT_25196 (Reactome)
CBP/p300REACT_25275 (Reactome)
CYLDmim-catalysisREACT_25235 (Reactome)
DAKArrowREACT_25160 (Reactome)
DDX58ArrowREACT_25235 (Reactome)
DDX58REACT_25191 (Reactome)
DDX58REACT_25357 (Reactome)
DHX58TBarREACT_25357 (Reactome)
E2 enzyme ArrowREACT_25252 (Reactome)
FADDREACT_25147 (Reactome)
IKK related kinases TBK1/IKK epsilonREACT_25179 (Reactome)
IKKA

IKKB

NEMO
REACT_24935 (Reactome)
IKKA

IKKB

NEMO
REACT_25134 (Reactome)
IPS-1 ATG5-ATG12 conjugateREACT_24982 (Reactome)
IPS-1 NLRX1TBarREACT_24957 (Reactome)
IRF1 Promotors of IFN alpha, IFN betaArrowREACT_25209 (Reactome)
IRF2 promoters of INF alpha, INF betaTBarREACT_25209 (Reactome)
IRF3 bound to IFN-beta promoterArrowREACT_25400 (Reactome)
IRF3-P IRF7-PArrowREACT_24983 (Reactome)
IRF3-P IRF7-PArrowREACT_25352 (Reactome)
IRF3-P IRF7-PREACT_25196 (Reactome)
IRF3-P IRF7-PREACT_25352 (Reactome)
IRF3-P dimer CBP/p300REACT_25153 (Reactome)
IRF3/ IRF7REACT_25170 (Reactome)
IRF7REACT_25308 (Reactome)
ISG15 RIG-I conjugateTBarREACT_25357 (Reactome)
ISG15

UBEIL/UbcH8

CEB1
REACT_25191 (Reactome)
ISGylated IRF3TBarREACT_24932 (Reactome)
ITCHREACT_25398 (Reactome)
ITCHmim-catalysisREACT_25398 (Reactome)
IkBs NFkBREACT_6848 (Reactome)
K48polyUb RIG-I/MDA5ArrowREACT_25252 (Reactome)
K48polyUb-TRAF3ArrowREACT_24974 (Reactome)
K48polyUbREACT_24974 (Reactome)
K48polyUbREACT_25398 (Reactome)
K63-UbArrowREACT_25055 (Reactome)
K63polyUb-TRAF3REACT_25364 (Reactome)
K63polyUbREACT_25220 (Reactome)
MAP3K1REACT_25003 (Reactome)
MAVSREACT_24957 (Reactome)
MAVSREACT_25223 (Reactome)
MDA5 DAKREACT_25160 (Reactome)
NFkB ComplexArrowREACT_6848 (Reactome)
NLRC5REACT_25113 (Reactome)
NLRX1REACT_25223 (Reactome)
OTUD5mim-catalysisREACT_25055 (Reactome)
PCBP2REACT_24967 (Reactome)
PIN1REACT_25077 (Reactome)
Phospho-NF-kappaB InhibitorArrowREACT_6848 (Reactome)
Promoter region of type-I IFN genesREACT_24975 (Reactome)
Promotor region of interferon betaREACT_25153 (Reactome)
REACT_24920 (Reactome) p-IRF7 dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes.
REACT_24932 (Reactome) PIN1 acts as a negative regulator of IFN induction. Its association with IRF3 leads to ubiquitin-mediated proteosomal degradation of IRF3. PIN1 on its own does not have ubiquitin activation, transfer or ligase activities. Exactly how this IRF3 degradation is achieved is unclear at present. Immunoprecipitation of ubiquitin followed by immunoblot analysis for IRF3 demonstrated that polyubiquitination of IRF3 was induced by RNA stimulation and that polyubiquitination was augmented by PIN1 expression and abrogated by expression of PIN1-specific shRNA.
REACT_24935 (Reactome) In Human, IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex and NFkB mediated antiviral responce are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO.[Solt et al 2009]; [Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it's remained unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.

This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.

IKK beta is the major IKK catalytic subunit for NF-kB activation. MEKK1 can activate both IKK-alpha (IKKA) and IKK-beta (IKKB) in vivo. MEKK1 phosphorylates Ser-176 and Ser-180 in IKKA and Ser-177 and Ser-181 in IKKB activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
REACT_24946 (Reactome) Procaspase-8/10 undergo dimerization and the subsequent conformational changes at the receptor complex results in the formation of catalytic active caspase dimers.
REACT_24957 (Reactome) Upon binding the dsRNA, RIG-I and MDA5 recruit downstream signal transducer, a mitochondria-bound protein: IPS-1/VISA/MAVS/CARDIF. This mitochondria-bound adaptor has been given four different names according to the various groups who identified it: MAVS, mitochondrial antiviral signaling; IPS-1, interferonbeta promoter stimulator 1; VISA, virus-induced signaling adaptor; CARDIF, CARD adaptor inducing IFNbeta. IPS-1 is an adaptor protein with an N-terminal CARD-like domain (CLD) and with this it associates with the CARD regions of RIG-I and MDA5 and mediate the induction of interferons.
REACT_24967 (Reactome) Poly(rC) binding protein 2 (PCB2), is one of the negative regulators of RIG-I/MDA5 signaling. It interacts with MAVS/IPS-1 and mediates its ubiquitin/proteasomal degradation by recruiting E3 ligase AIP4/ITCHY.
REACT_24974 (Reactome) TRAF3 is dual regulated by DUBA and TRIAD3A. TRAF3 K63-polyubiquitin is removed by DUBA to disrupt TRAF3-TBK1/IKKi interactions. TRAF3 then undergoes a late phase K48-linked polyubiquitination by TRIAD3A, leading to TRAF3 proteasomal degradation. Thus TRIAD3A acts as a E3- ubiquitin ligase that negatively regulates RLR pathway.
REACT_24975 (Reactome) IRF7 and VAF transcription factors binds to IFN-alpha and IFN-beta promoter regions and induce the IFN-alpha and beta mRNA.
REACT_24982 (Reactome) Autophagy protein 5 (ATG5) and autophagy-related protein 12 (ATG12) conjugate negatively regulates the type I IFN production pathway by directly associating with RIG-I/MDA5 and IPS-1 through the caspase recruitment domains (CARDs). The ATG5-ATG12 conjugate intercalates between the CARDs of RIG-I/MDA5 and IPS-1 and inhibits signal transmission, resulting in suppression of type I IFN production and innate antiviral immune responses.
REACT_24983 (Reactome) Phosphorylation of these transcription factors IRF3 and IRF7 results in a conformational change that allows their dimerization to form homo- or hetero dimers. Each of the three different combinations of dimers (IRF3:IRF3, IRF7:IRF7 and IRF3:IRF7) may selectively effect the transcription of IFN-alpha gene subfamilies and IFN-beta genes.
REACT_24986 (Reactome) TRAF family member-associated NF-kB activator (TANK also known as I-TRAF) plays an important role in IFN induction through both RIG-I and Toll-like receptor-dependent pathways. TANK has been identified as a TRAF6 binding protein. Transient transfection experiments in 293T cells revealed that TRAF6 associates with IPS-1, TBK1, IKKi, and TANK (Konno H et al).
REACT_24999 (Reactome) Processing of caspases is required for activation of downstream signaling and dsRNA stimulation inducese the processing of these caspases. The nonapoptotic caspase function of both caspase-8 and -10 does not require the protease activity and the DED-containing prodomains are sufficient for NF-kB activation.
REACT_25003 (Reactome) TRAF6 requires MEKK1 to activate NF-kB and MEKK1 may interact with TRAF6, which in turn contribute to the activation of IKK and MAPKK, leading to the activation of NF-kB and AP-1. (Yoshida et al)
REACT_25051 (Reactome) TRAF3 binds with both IPS-1 and downstream interferon regulatory factor 3/7 (IRF3/7) kinases TBK1 and IKK-epsilon (IKKi) and thus serves as a critical link between RIG-I/MDA5 adaptors and downstream regulatory kinases important for interferon regulatory factor (IRF) activation (Oganesyan et al).
SIKE (for Suppressor of IKKepsilon) interacts with IKKepsilon and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection. Overexpression of SIKE disrupted the interactions of IKKepsilon or TBK1 with RIG-I.
REACT_25055 (Reactome) Deubiquitinating enzyme A (DUBA), an ovarian tumor (OTU) domain-containing deubiquitinating enzyme, is a negative regulator of type I IFN production. TRAF3 is one of the DUBA interacting protein and expression of DUBA increases the cleavage of K63-linked ubiquitin chains of TRAF3. TRAF3 ubiquitination facilitates the recruitment of downstream signaling components and DUBA mediated removal of ubiquitin chains reduce the TRAF3-TBK1 interaction and subsequent blockade of IRF3 and IRF7 phosphorylation.
REACT_25077 (Reactome) Two cluster of serine residues in the C-terminus of IRF3 are essential for its activation. Cluster 1, comprising Ser385 and Ser386, is essential for the formation of IRF3 dimers. The second cluster include a series of serine and threonine residues between Ser396 and Ser405. Phosphorylation of residues in both clusters has been noted in response to virus infection and dsRNA treatment, and the IKKi/TBK1 kinase complex has been shown to phosphorylate both clusters.
Yamaoka et al has shown that IRF3 is also phosphorylated on Ser339 after dsRNA stimulation, however this phosphorylation is associated with destabilization rather than activation of IRF3. This Ser339 precedes a proline residue 340 (Pro340) and this serine-proline motif acts as a binding site for the protein PIN1, a peptidyl-prolyl-isomerase. PIN1 consist of two distinct domains, a short N-terminal WW domain and a C-terminal catalytic domain. The WW domain of PIN1 is involved in binding the ser339-pro340 region. Yamaoka et al showed that exogenous expression of PIN1 suppresses IRF3 activation and type I interferon production and, conversely, that siRNA silencing of PIN1 leads to enhancement of IRF3 activation and IFNB production.
REACT_25079 (Reactome) TANK acts as an adapter protein and regulates the assembly of TBK1/IKK epsilon complex with upstream signaling molecules. SIKE (for Suppressor of IKKepsilon) interacts with IKKepsilon and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection. Overexpression of SIKE disrupted the interactions of IKKepsilon or TBK1 with RIG-1.
REACT_25099 (Reactome) p-IRF7 dimers after translocation into nucleus interact with the coactivators p300 and CBP (CREB-binding protein) to form a stable complex. This interaction further increases the transcriptional activity of IRF7.
REACT_25113 (Reactome) NLRC5 competes with IPS-1 for binding to the CARD domain of RIG-I/MDA5. NLRC5 specifically recognize the CARD domains of RIG-I/MDA5 when the CARD domains become accessible after viral infection, leading to dampened activation of IRF3.
REACT_25134 (Reactome) The molecular mechanisms by which caspase-8/10 attribute to NF-kB signaling is unclear. Caspase-8 might act as a scaffolding protein by bringing the IKK-complex in close proximity to its activator TAK1. The prodomain of Caspase-8 could interact with IKK2 in the IKK complex whereas the protease homology domain failed to do so. These results indicate that the interaction of the DEDs-containing prodomain of caspase-8 with the IKKs may be crucial for the NF-kB induction by caspase-8.
REACT_25147 (Reactome) Receptor-interacting protein 1 (RIP1) and Fas-Associated Death Domain (FADD) are death domain (DD)-containing proteins. These proteins interact with IPS-1 and activate NF-kB through interaction and activation of caspase-8 and caspase-10.
REACT_25153 (Reactome) IRF3:CBP/p300 complex binds specifically to IFN-beta promoter region and induces IFN-beta mRNA expression.
REACT_25160 (Reactome) MDA5 is the closest relative of RIG-I and contains two CARD-like regions, a DExD/H helicase domain, and a C-terminal region similar to the RD of RIG-I. MDA5 with its C-terminal domain (CTD) preferentially binds dsRNA with blunt ends, but does not associate with dsRNA with either 5' or 3' overhangs. Upon binding dsRNA, MDA5 is presumed to undergo structural alteration and, thereby unmask the CARDs enabling them to recruit downstream signal transducer proteins. Dihydroxyacetone kinase (DAK) binds to the CARD domains of MDA5 and acts as a negative regulator of MAD5. It is released upon the conformational change induced by viral RNA binding, allowing the MDA5 CARD domains to bind to IPS-1 CARD.
REACT_25167 (Reactome) Caspase-8 (casp-8) and caspase-10 (casp-10) are involved in RIG-I/MDA5-dependent antiviral immune responses. Caspase-8/10 activation contributes to NF-kB activation in response to viral dsRNA.
Caspase-8/10 are synthesized as zymogens (procaspases), containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domain separated by a smaller linker region. FADD plays a crucial role in the recruitment and activation of procaspase-8/10. The two DED domains of procaspase-8/10 interacts with DED domain of FADD.
REACT_25170 (Reactome) IRF3 and IRF7 (IRF3/IRF7) are the two major members of the interferon regulatory factor (IRF) family, involved in modulating the IFN gene expression. However, their roles are different in these processes. In the early phase of viral infection, preexisting IRF-3 is activated and induces expression of IFN beta and IFN alpha4. These early produced IFNs transcriptionally induce IRF-7, and upon viral infection, the induced high-level IRF-7 is activated and transactivates multiple IFN genes, leading to robust production of IFNs in response to viral infection. IPS-1 interacts with both IRF3 and IRF7 and recruits them to RIG-1. TBK1/IKKi kinases phosphorylate and activate IRF3/IRF7.
REACT_25179 (Reactome) TAX1BP1 functions as an adaptor molecule for A20 to terminate antiviral signaling. TAX1BP1 and A20 blocked antiviral signaling by disrupting K63-linked polyubiquitination of TBK1-IKKi.
REACT_25191 (Reactome) ISG15 is a ubiquitin (Ub)-like protein which is conjugated to intracellular proteins via an isopeptide bond. Similar to ubiquitination, the conjugation of ISG15 (ISGylation) requires a three-step process, involving an E1 activating enzyme (UBE1L), an E2 conjugating enzyme (UbcM8/H8), and HERC5/Ceb1 an IFN-inducible ISG15-specific E3 ligase. ISG15 conjugation may play an important regulatory role in IFN-mediated antiviral responses. IFN induces ISG15 conjugation to RIG-I protein and lowers cellular levels of unconjugated RIG-I protein and, thus, negatively regulates RIG-I-mediated antiviral signaling. ISGylated RIG-I protein becomes subject to an irreversible biochemical process, such as proteolysis or proteasomeal degradation.
REACT_25196 (Reactome) IRF3 and IRF7 associate with each other and they further interact with the coactivators CBP and p300 to form a more potent transcription factor complex called VAF (virus-activated factor).
REACT_25209 (Reactome) The Interferon alpha and beta genes are transcribed and translated yielding IFNA and IFNB which are secreted. This process is positively regulated by Interferon Regulatory Factor 1 and negatively regulated by Interferon Regulatory Factor 2, which compete for binding to the same regulatory element (Harada et al. 1989).
REACT_25220 (Reactome) On viral infection RIG-I undergoes robust ubiquitination at its N-terminal CARD region. TRIM25 a member of tripartite motif (TRIM) protein family and Riplet/RNF135/REUL are the ubiquitin E3 ligases involved in K-63-linked polyubiquitination of RIG-I. TRIM25 contains a cluster of domains including a RING-finger domain, a B box/coiled-coil domain and a SPRY domain. The interaction is mediated by the SPRY domain of TRIM25 and the N-terminal CARDs of RIG-I. The polyubiquitin chains added by TRIM25 are unanchored Lys-172 (K-172) residue of RIG-I is critical for efficient TRIM25-mediated ubiquitination and for IPS-1 binding, as well as the ability of RIG-I to induce antiviral signal transduction. RING-finger protein, RNF135 specifically associate with RIG-I through its PRY and SPRY domains. The Lys 154, 164, and 172 residues of the RIG-I CARD domain were determined to be critical for efficient RNF135-mediated ubiquitination and for the ability of RIG-I to induce antiviral signal transduction. (Michaela et al, Goa et al)
REACT_25223 (Reactome) NLRX1 is a member of nucleotide-binding domain and leucine-rich repeat containing (NLR) protein family. NLRX1 competes with RIG-I for IPS-1 interaction and has been identified as a negative regulator of RLR signaling. NLRX1 resides at the outer mitochondrial membrane where IPS-1 is located and this interaction is mediated by the CARD region of IPS-1 and a putative nucleotide-binding domain (NBD) of NLRX1. This interaction between NLRX1 and IPS-1 prevents the association between RIG-1/MDA5 and IPS-1.
REACT_25235 (Reactome) CYLD is an ovarian tumor (OTU) domain-containing deubiquitinating enzyme (DUB) and has been identified as a negative regulator of RIG-I mediated antiviral signaling. CYLD associates with the CARD domain of RIG-I and removes K63-linked ubiquitin from the RIG-I CARDs that are conjugated by the E3 ubiquitin ligase, TRIM25 and RNF135.
REACT_25252 (Reactome) RNF125 acts as an E3-ubiquitin ligase that conjugates with RIG-I, MDA5 and IPS-1 and mediate their proteosomal degradation. UbcH1, UbcH5a, UbcH5b, and UbcH5c function as an E2 enzyme and conjugate ubiquitin to RNF125 and RIG-1 via K48. Among these enzymes UbcH5c is the major E2 enzyme showing enhanced ubiquitin conjugation to RIG-I. RNF125 mediated ubiquitination of RIG-I/MDA5 and IPS1 inhibits RIG-I signaling by shunting these proteins toward proteasomal degradation.
REACT_25262 (Reactome) IPS-1 interacts with TRAF2 and TRAF6 through its consensus TRAF-interaction motif (TIM) (TRAF2 143-PVGET-147 and TRAF6 153-PGENSE-158 & 455-PEENEY-460). Although IPS-1 can bind to both TRAF6 and TRAF2, TRAF2 binding is not required for IPS-1 activation of NF-kB.
REACT_25275 (Reactome) Phosphorylated IRF3 dimer translocated to the nucleus interacts with the coactivator CBP/p300. This interaction prevents the export of activated IRF3 dimer from nucleus and it may also alter the conformation of the DNA binding domain of IRF3, and induce specific DNA binding of IRF3.
REACT_25292 (Reactome) Phosphorylation stimulates the C-terminal autoinhibitory domain of IRF7 to attain a highly extended conformation triggering dimerization through extensive contacts to a second IRF7 subunit.
REACT_25308 (Reactome) TRAF6 associates with and activates IRF7 but not IRF3.
REACT_25327 (Reactome) IRF7 is activated through phosphorylation of residues Ser477 and Ser479 by TBK1/IKKi kinase complex.
REACT_25352 (Reactome) Phosphorylated IRF dimers after dimerization translocates into the nucleus and associate with general coactivators like CBP/p300 and bind to type-I IFN promoter region.
REACT_25357 (Reactome) RIG-I has two copies of caspase recruitment domain (CARD) in its N-terminus, DExD/H helicase domain with an ATP binding motif in the middle and a repressor domain (RD) in the C-terminus. In the absence of appropriate stimulation, RIG-I is in a 'closed' conformation in which the repressor domain phyically interacts with the helicase domain masking CARD. Upon viral infection the free triphosphate structure at the 5' end of the viral RNAs activate RIG-I by binding to its RNA helicase domain. This provokes change in RIG-I conformation exposing the CARD leading to RIG-I dimerization and allowing it to interact with the mitochondria-bound interferon beta promoter stimulator-1 (IPS-1).
REACT_25364 (Reactome) TRAF3 a E3 ligase for K63-linked polyubiquitination, is one of the critical molecules required for mediating IPS-1 dependent type I IFN production. TRAF3 interacts directly with IPS-1 through the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) with in IPS-1.
REACT_25368 (Reactome) Human IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring 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 (Ser396—Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). 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].
Since the number of serine residues involved into IRF activation remains unclear this reaction represents a minimum stoichiometry to achieve the phosphorylation of at least 3 Ser residues per each IRF transcription factor. [Lin et al 2000, Ning et al 2008]
REACT_25398 (Reactome) On viral infection PCB2 binds MAVS/IPS-1 and recruits the HECT domain-containing E3 ligase AIP4/ITCHY. AIP4 catalyses K48-polyubiquitination and degradation of MAVS. PCBP2 overexpression enhanced the interaction between MAVS and AIP4 and led to more degradation of MAVS. MAVS/IPS-1 regulation is very important in preventing excessive harmful immune responses.
REACT_25400 (Reactome) The IFN-beta genes are transcribed and translated yielding IFNB proteins which are secreted. This process is positively regulated by IRF3:CBP/p300 transcription factor complex.
REACT_6848 (Reactome) In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits.

A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB.

REACT_6906 (Reactome) NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NFkappa-B2), All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefor, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.
RIG-I E3 ubiquitin ligasesREACT_25220 (Reactome)
RIG-I E3 ubiquitin ligasesmim-catalysisREACT_25220 (Reactome)
RIPK1REACT_25147 (Reactome)
RNF125 E2 enzyme mim-catalysisREACT_25252 (Reactome)
RNF125ArrowREACT_25252 (Reactome)
SIKE1ArrowREACT_25051 (Reactome)
SIKE1ArrowREACT_25079 (Reactome)
TANKREACT_24986 (Reactome)
TAX1BP1 TNFAIP3REACT_25179 (Reactome)
TBK1/IKKi SIKE1REACT_25051 (Reactome)
TBK1/IKKi SIKE1REACT_25079 (Reactome)
TRAF2 and TRAF6REACT_25262 (Reactome)
UbArrowREACT_25235 (Reactome)
VAF/pIRF7 CBP/p300 bound to type I IFN gene promoterArrowREACT_25209 (Reactome)
VAF/pIRF7 CBP/p300REACT_24975 (Reactome)
Viral dsRNA REACT_25160 (Reactome)
Viral dsRNA REACT_25357 (Reactome)
dsRNA MDA5ArrowREACT_25160 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1

TRAF3
ArrowREACT_25055 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1

TRAF3
REACT_24974 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1 Ub-TRAF3 TBK1/IKKi

IRF3/IRF7
REACT_25368 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1 Ub-TRAF3 TBK1/IKKi

IRF3/IRF7
mim-catalysisREACT_25368 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1 Ub-TRAF3

TBK1/IKKi
ArrowREACT_25051 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1 Ub-TRAF3

TBK1/IKKi
ArrowREACT_25368 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1 Ub-TRAF3

TBK1/IKKi
REACT_25170 (Reactome)
dsRNA

RIG-1/MDA5 IPS-1

Ub-TRAF3
REACT_25051 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

PCBP2
REACT_25398 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 RIP-1/FADD

Procasp-8/10
REACT_24946 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 RIP-1/FADD

procaspase-8/10 dimer
mim-catalysisREACT_24999 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

RIP-1/FADD
REACT_25167 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6

MEKK1
mim-catalysisREACT_24935 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK TBK1/IKKi

IRF7
REACT_25327 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK TBK1/IKKi

IRF7
mim-catalysisREACT_25327 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK

TBK1/IKKi
ArrowREACT_25079 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK

TBK1/IKKi
ArrowREACT_25327 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK

TBK1/IKKi
REACT_25308 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1 TRAF2/TRAF6

TANK
REACT_25079 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

TRAF2/TRAF6
REACT_24986 (Reactome)
dsRNA

RIG-I/MDA5 IPS-1

TRAF2/TRAF6
REACT_25003 (Reactome)
dsRNA

RIG-I/MDA5

IPS-1
ArrowREACT_24974 (Reactome)
dsRNA

RIG-I/MDA5

IPS-1
REACT_24967 (Reactome)
dsRNA

RIG-I/MDA5

IPS-1
REACT_25147 (Reactome)
dsRNA

RIG-I/MDA5

IPS-1
REACT_25262 (Reactome)
dsRNA

RIG-I/MDA5

IPS-1
REACT_25364 (Reactome)
dsRNA

RIG-I/MDA5

NLRC5
TBarREACT_24957 (Reactome)
dsRNA

RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD

Casp-8/10 prodomain
ArrowREACT_24999 (Reactome)
dsRNA

RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD

Casp-8/10 prodomain
REACT_25134 (Reactome)
dsRNA RIG-I/MDA5REACT_24957 (Reactome)
dsRNA RIG-I/MDA5REACT_24982 (Reactome)
dsRNA RIG-I/MDA5REACT_25113 (Reactome)
dsRNA bound to RIG-IREACT_25220 (Reactome)
p-2S-IRF7 p-2S-IRF7ArrowREACT_24983 (Reactome)
p-2S-IRF7 p-2S-IRF7ArrowREACT_25352 (Reactome)
p-2S-IRF7 p-2S-IRF7REACT_25099 (Reactome)
p-2S-IRF7 p-2S-IRF7REACT_25352 (Reactome)
p-IRF3 p-IRF3REACT_25077 (Reactome)
p-S477,S479-IRF7ArrowREACT_25327 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3ArrowREACT_24983 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3ArrowREACT_25352 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3REACT_25275 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3REACT_25352 (Reactome)
phosphorylated IRF3/IRF7ArrowREACT_25368 (Reactome)
procaspase-8/10REACT_24946 (Reactome)
procaspase-8/10REACT_25167 (Reactome)
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