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

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1. Lee FS, Peters RT, Dang LC, Maniatis T.; ''MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta.''; PubMed Europe PMC Scholia
2. Bowie AG, Unterholzner L.; ''Viral evasion and subversion of pattern-recognition receptor signalling.''; PubMed Europe PMC Scholia
3. Gao D, Yang YK, Wang RP, Zhou X, Diao FC, Li MD, Zhai ZH, Jiang ZF, Chen DY.; ''REUL is a novel E3 ubiquitin ligase and stimulator of retinoic-acid-inducible gene-I.''; PubMed Europe PMC Scholia
4. Broquet AH, Hirata Y, McAllister CS, Kagnoff MF.; ''RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-infected intestinal epithelium.''; PubMed Europe PMC Scholia
5. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S.; ''Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.''; PubMed Europe PMC Scholia
6. Mori M, Yoneyama M, Ito T, Takahashi K, Inagaki F, Fujita T.; ''Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation.''; PubMed Europe PMC Scholia
7. Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE, Zimmermann AG, Accavitti-Loper MA, Madden VJ, Sun L, Ye Z, Lich JD, Heise MT, Chen Z, Ting JP.; ''NLRX1 is a regulator of mitochondrial antiviral immunity.''; PubMed Europe PMC Scholia
8. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M.; ''Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.''; PubMed Europe PMC Scholia
9. Maelfait J, Beyaert R.; ''Non-apoptotic functions of caspase-8.''; PubMed Europe PMC Scholia
10. Li X, Massa PE, Hanidu A, Peet GW, Aro P, Savitt A, Mische S, Li J, Marcu KB.; ''IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program.''; PubMed Europe PMC Scholia
11. Yoneyama M, Fujita T.; ''RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity.''; PubMed Europe PMC Scholia
12. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
13. Lin R, Mamane Y, Hiscott J.; ''Structural and functional analysis of interferon regulatory factor 3: localization of the transactivation and autoinhibitory domains.''; PubMed Europe PMC Scholia
14. Huang J, Liu T, Xu LG, Chen D, Zhai Z, Shu HB.; ''SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways.''; PubMed Europe PMC Scholia
15. Lamkanfi M, Declercq W, Vanden Berghe T, Vandenabeele P.; ''Caspases leave the beaten track: caspase-mediated activation of NF-kappaB.''; PubMed Europe PMC Scholia
16. Pomerantz JL, Baltimore D.; ''NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.''; PubMed Europe PMC Scholia
17. Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O'Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM.; ''DUBA: a deubiquitinase that regulates type I interferon production.''; PubMed Europe PMC Scholia
18. Tsuchida T, Kawai T, Akira S.; ''Inhibition of IRF3-dependent antiviral responses by cellular and viral proteins.''; PubMed Europe PMC Scholia
19. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB.; ''VISA is an adapter protein required for virus-triggered IFN-beta signaling.''; PubMed Europe PMC Scholia
20. Konno H, Yamamoto T, Yamazaki K, Gohda J, Akiyama T, Semba K, Goto H, Kato A, Yujiri T, Imai T, Kawaguchi Y, Su B, Takeuchi O, Akira S, Tsunetsugu-Yokota Y, Inoue J.; ''TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA.''; PubMed Europe PMC Scholia
21. Pothlichet J, Meunier I, Davis BK, Ting JP, Skamene E, von Messling V, Vidal SM.; ''Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells.''; PubMed Europe PMC Scholia
22. Solis M, Goubau D, Romieu-Mourez R, Genin P, Civas A, Hiscott J.; ''Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages.''; PubMed Europe PMC Scholia
23. Solt LA, Madge LA, May MJ.; ''NEMO-binding domains of both IKKalpha and IKKbeta regulate IkappaB kinase complex assembly and classical NF-kappaB activation.''; PubMed Europe PMC Scholia
24. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ.; ''Caspase-10 is an initiator caspase in death receptor signaling.''; PubMed Europe PMC Scholia
25. Seth RB, Sun L, Ea CK, Chen ZJ.; ''Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.''; PubMed Europe PMC Scholia
26. Oshiumi H, Matsumoto M, Hatakeyama S, Seya T.; ''Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection.''; PubMed Europe PMC Scholia
27. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N.; ''IRF family of transcription factors as regulators of host defense.''; PubMed Europe PMC Scholia
28. Takahasi K, Suzuki NN, Horiuchi M, Mori M, Suhara W, Okabe Y, Fukuhara Y, Terasawa H, Akira S, Fujita T, Inagaki F.; ''X-ray crystal structure of IRF-3 and its functional implications.''; PubMed Europe PMC Scholia
29. Yoneyama M, Fujita T.; ''Function of RIG-I-like receptors in antiviral innate immunity.''; PubMed Europe PMC Scholia
30. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM.; ''FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.''; PubMed Europe PMC Scholia
31. Diao F, Li S, Tian Y, Zhang M, Xu LG, Zhang Y, Wang RP, Chen D, Zhai Z, Zhong B, Tien P, Shu HB.; ''Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase.''; PubMed Europe PMC Scholia
32. Panne D, McWhirter SM, Maniatis T, Harrison SC.; ''Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch.''; PubMed Europe PMC Scholia
33. Bonizzi G, Karin M.; ''The two NF-kappaB activation pathways and their role in innate and adaptive immunity.''; PubMed Europe PMC Scholia
34. Paz S, Sun Q, Nakhaei P, Romieu-Mourez R, Goubau D, Julkunen I, Lin R, Hiscott J.; ''Induction of IRF-3 and IRF-7 phosphorylation following activation of the RIG-I pathway.''; PubMed Europe PMC Scholia
35. Shikama Y, Yamada M, Miyashita T.; ''Caspase-8 and caspase-10 activate NF-kappaB through RIP, NIK and IKKalpha kinases.''; PubMed Europe PMC Scholia
36. Qin BY, Liu C, Lam SS, Srinath H, Delston R, Correia JJ, Derynck R, Lin K.; ''Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation.''; PubMed Europe PMC Scholia
37. Arimoto K, Takahashi H, Hishiki T, Konishi H, Fujita T, Shimotohno K.; ''Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125.''; PubMed Europe PMC Scholia
38. Parvatiyar K, Barber GN, Harhaj EW.; ''TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases.''; PubMed Europe PMC Scholia
39. Kawagoe T, Takeuchi O, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S.; ''TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis.''; PubMed Europe PMC Scholia
40. Guo B, Cheng G.; ''Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK.''; PubMed Europe PMC Scholia
41. Jacobs MD, Harrison SC.; ''Structure of an IkappaBalpha/NF-kappaB complex.''; PubMed Europe PMC Scholia
42. Wathelet MG, Lin CH, Parekh BS, Ronco LV, Howley PM, Maniatis T.; ''Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo.''; PubMed Europe PMC Scholia
43. Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A, Xu M, Chen ZJ.; ''Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity.''; PubMed Europe PMC Scholia
44. Yoneyama M, Fujita T.; ''Structural mechanism of RNA recognition by the RIG-I-like receptors.''; PubMed Europe PMC Scholia
45. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S.; ''IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.''; PubMed Europe PMC Scholia
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

External references

DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
AGER	Protein	Q15109 (Uniprot-TrEMBL)
AGER ligands AGER	Complex	REACT_24620 (Reactome)
APP	Protein	P05067 (Uniprot-TrEMBL)
ATG12	Protein	O94817 (Uniprot-TrEMBL)
ATG5	Protein	Q9H1Y0 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated IKK Complex	Complex	REACT_7826 (Reactome)
CASP10	Protein	Q92851 (Uniprot-TrEMBL)
CASP8	Protein	Q14790 (Uniprot-TrEMBL)
CBP/p300 pIRF7 pIRF7	Complex	REACT_25574 (Reactome)
CBP/p300	Protein	REACT_25880 (Reactome)
CHUK	Protein	O15111 (Uniprot-TrEMBL)
CREBBP	Protein	Q92793 (Uniprot-TrEMBL)
CYLD	Protein	Q9NQC7 (Uniprot-TrEMBL)
DAK	Protein	Q3LXA3 (Uniprot-TrEMBL)
DAK	Protein	Q3LXA3 (Uniprot-TrEMBL)
DDX58	Protein	O95786 (Uniprot-TrEMBL)
DDX58/IFIH1	Protein	REACT_25428 (Reactome)
DDX58	Protein	O95786 (Uniprot-TrEMBL)
DHX58	Protein	Q96C10 (Uniprot-TrEMBL)
E2 enzyme	Protein	REACT_26340 (Reactome)
EP300	Protein	Q09472 (Uniprot-TrEMBL)
FADD	Protein	Q13158 (Uniprot-TrEMBL)
FADD	Protein	Q13158 (Uniprot-TrEMBL)
HERC5	Protein	Q9UII4 (Uniprot-TrEMBL)
HMGB1	Protein	P09429 (Uniprot-TrEMBL)
IFIH1	Protein	Q9BYX4 (Uniprot-TrEMBL)
IFN alpha/beta	Protein	REACT_26595 (Reactome)
IFNB1	Protein	P01574 (Uniprot-TrEMBL)
IKBKB	Protein	O14920 (Uniprot-TrEMBL)
IKBKE	Protein	Q14164 (Uniprot-TrEMBL)
IKBKG	Protein	Q9Y6K9 (Uniprot-TrEMBL)
IKK related kinases TBK1/IKK epsilon	Protein	REACT_21591 (Reactome)
IKKA IKKB NEMO	Complex	REACT_7693 (Reactome)
IPS-1 ATG5-ATG12 conjugate	Complex	REACT_25931 (Reactome)
IPS-1 NLRX1	Complex	REACT_26115 (Reactome)
IRF1 Promotors of IFN alpha, IFN beta	Complex	REACT_26239 (Reactome)
IRF1	Protein	P10914 (Uniprot-TrEMBL)
IRF2 promoters of INF alpha, INF beta	Complex	REACT_26555 (Reactome)
IRF2	Protein	P14316 (Uniprot-TrEMBL)
IRF3	Protein	Q14653 (Uniprot-TrEMBL)
IRF3 bound to IFN-beta promoter	Complex	REACT_25617 (Reactome)
IRF3-P IRF7-P	Complex	REACT_26495 (Reactome)
IRF3-P IRF7-P	Complex	REACT_26957 (Reactome)
IRF3-P dimer CBP/p300	Complex	REACT_26303 (Reactome)
IRF3/ IRF7	Protein	REACT_21735 (Reactome)
IRF7	Protein	Q92985 (Uniprot-TrEMBL)
IRF7	Protein	Q92985 (Uniprot-TrEMBL)
ISG15 RIG-I conjugate	Complex	REACT_26209 (Reactome)
ISG15 UBEIL/UbcH8 CEB1	Complex	REACT_26934 (Reactome)
ISG15	Protein	P05161 (Uniprot-TrEMBL)
ISGylated IRF3	Complex	REACT_27520 (Reactome)
ITCH	Protein	Q96J02 (Uniprot-TrEMBL)
ITCH	Protein	Q96J02 (Uniprot-TrEMBL)
IkBs NFkB	Complex	REACT_7272 (Reactome)
K48polyUb RIG-I/MDA5	Complex	REACT_25791 (Reactome)
K48polyUb-DDX58	Protein	O95786 (Uniprot-TrEMBL)
K48polyUb-IFIH1	Protein	Q9BYX4 (Uniprot-TrEMBL)
K48polyUb-MAVS	Protein	Q7Z434 (Uniprot-TrEMBL)
K48polyUb-RNF125	Protein	Q96EQ8 (Uniprot-TrEMBL)
K48polyUb-TRAF3	Protein	Q13114 (Uniprot-TrEMBL)
K48polyUb-TRAF3	Complex	Q13114 (Uniprot-TrEMBL)
K48polyUb		REACT_24769 (Reactome)
K63-Ub	Protein	REACT_21627 (Reactome)
K63polyUb-DDX58	Protein	O95786 (Uniprot-TrEMBL)
K63polyUb-DDX58	Complex	O95786 (Uniprot-TrEMBL)
K63polyUb-TRAF3	Protein	Q13114 (Uniprot-TrEMBL)
K63polyUb-TRAF3	Complex	Q13114 (Uniprot-TrEMBL)
K63polyUb		REACT_21645 (Reactome)
MAP3K1	Protein	Q13233 (Uniprot-TrEMBL)
MAVS	Protein	Q7Z434 (Uniprot-TrEMBL)
MAVS	Protein	Q7Z434 (Uniprot-TrEMBL)
MDA5 DAK	Complex	REACT_25465 (Reactome)
N-epsilon-	Metabolite	CHEBI:60125 (ChEBI)
NECML	Metabolite	CHEBI:53014 (ChEBI)
NFKB1	Protein	P19838 (Uniprot-TrEMBL)
NFKB2	Protein	Q00653 (Uniprot-TrEMBL)
NFKBIA	Protein	P25963 (Uniprot-TrEMBL)
NFKBIB	Protein	Q15653 (Uniprot-TrEMBL)
NFkB Complex	Complex	REACT_7108 (Reactome)
NFkB Complex	Complex	REACT_7143 (Reactome)
NLRC5	Protein	Q86WI3 (Uniprot-TrEMBL)
NLRC5	Protein	Q86WI3 (Uniprot-TrEMBL)
NLRX1	Protein	Q86UT6 (Uniprot-TrEMBL)
NLRX1	Protein	Q86UT6 (Uniprot-TrEMBL)
OTUD5	Protein	Q96G74 (Uniprot-TrEMBL)
PCBP2	Protein	Q15366 (Uniprot-TrEMBL)
PCBP2	Protein	Q15366 (Uniprot-TrEMBL)
PIN1	Protein	Q13526 (Uniprot-TrEMBL)
PIN1	Protein	Q13526 (Uniprot-TrEMBL)
Peptide	Metabolite	CHEBI:16670 (ChEBI)
Phospho-NF-kappaB Inhibitor	Protein	REACT_7645 (Reactome)
Promoter region of type-I IFN genes		REACT_25653 (Reactome)
Promotor region of interferon beta		REACT_25836 (Reactome)
RELA	Protein	Q04206 (Uniprot-TrEMBL)
RIG-I E3 ubiquitin ligases	Protein	REACT_25644 (Reactome)
RIPK1	Protein	Q13546 (Uniprot-TrEMBL)
RIPK1	Protein	Q13546 (Uniprot-TrEMBL)
RNF125 E2 enzyme	Complex	REACT_25756 (Reactome)
RNF125	Protein	Q96EQ8 (Uniprot-TrEMBL)
RNF135	Protein	Q8IUD6 (Uniprot-TrEMBL)
S100A12	Protein	P80511 (Uniprot-TrEMBL)
S100B	Protein	P04271 (Uniprot-TrEMBL)
SAA1	Protein	P0DJI8 (Uniprot-TrEMBL)
SIKE1	Protein	Q9BRV8 (Uniprot-TrEMBL)
SIKE1	Protein	Q9BRV8 (Uniprot-TrEMBL)
TANK	Protein	Q92844 (Uniprot-TrEMBL)
TANK	Protein	Q92844 (Uniprot-TrEMBL)
TAX1BP1 TNFAIP3 TBK1/IKKi	Complex	REACT_25569 (Reactome)
TAX1BP1 TNFAIP3	Complex	REACT_26309 (Reactome)
TAX1BP1	Protein	Q86VP1 (Uniprot-TrEMBL)
TBK1	Protein	Q9UHD2 (Uniprot-TrEMBL)
TBK1/IKKi SIKE1	Complex	REACT_25799 (Reactome)
TNFAIP3	Protein	P21580 (Uniprot-TrEMBL)
TRAF2	Protein	Q12933 (Uniprot-TrEMBL)
TRAF2 and TRAF6	Protein	REACT_26063 (Reactome)
TRAF3	Protein	Q13114 (Uniprot-TrEMBL)
TRAF6	Protein	Q9Y4K3 (Uniprot-TrEMBL)
TRIM25	Protein	Q14258 (Uniprot-TrEMBL)
UBA7	Protein	P41226 (Uniprot-TrEMBL)
UBE2L6	Protein	O14933 (Uniprot-TrEMBL)
Ub	Protein	REACT_3316 (Reactome)
VAF	Complex	REACT_25426 (Reactome)
VAF/pIRF7 CBP/p300 bound to type I IFN gene promoter	Complex	REACT_26244 (Reactome)
VAF/pIRF7 CBP/p300	Complex	REACT_25775 (Reactome)
Viral dsRNA		REACT_6589 (Reactome)
dsRNA MDA5	Complex	REACT_26245 (Reactome)
dsRNA RIG-1/MDA5 IPS-1 TRAF3	Complex	REACT_25597 (Reactome)
dsRNA RIG-1/MDA5 IPS-1 Ub-TRAF3 TBK1/IKKi IRF3/IRF7	Complex	REACT_25519 (Reactome)
dsRNA RIG-1/MDA5 IPS-1 Ub-TRAF3 TBK1/IKKi	Complex	REACT_26022 (Reactome)
dsRNA RIG-1/MDA5 IPS-1 Ub-TRAF3	Complex	REACT_26564 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 ATG5-ATG12	Complex	REACT_26782 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 PCBP2	Complex	REACT_25961 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 RIP-1/FADD Procasp-8/10	Complex	REACT_26650 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 RIP-1/FADD procaspase-8/10 dimer	Complex	REACT_26858 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 RIP-1/FADD	Complex	REACT_26077 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 TRAF2/TRAF6 MEKK1	Complex	REACT_26122 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK TBK1/IKKi IRF7	Complex	REACT_26674 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK TBK1/IKKi	Complex	REACT_25493 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK	Complex	REACT_27050 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 TRAF2/TRAF6	Complex	REACT_26067 (Reactome)
dsRNA RIG-I/MDA5 IPS-1	Complex	REACT_26220 (Reactome)
dsRNA RIG-I/MDA5 K48 Ub-IPS-1 PCBP2 AIP4	Complex	REACT_26024 (Reactome)
dsRNA RIG-I/MDA5 NLRC5	Complex	REACT_26732 (Reactome)
dsRNA RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD Casp-8/10 prodomain IKK complex	Complex	REACT_27017 (Reactome)
dsRNA RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD Casp-8/10 prodomain	Complex	REACT_26324 (Reactome)
dsRNA RIG-I/MDA5	Complex	REACT_25628 (Reactome)
dsRNA Ub-RIG-I TRIM25	Complex	REACT_26009 (Reactome)
dsRNA bound to RIG-I	Complex	REACT_25966 (Reactome)
p-2S-IRF7 p-2S-IRF7	Complex	REACT_21640 (Reactome)
p-2S-IRF7 p-2S-IRF7	Complex	REACT_21965 (Reactome)
p-4S,T404-IRF3	Protein	Q14653 (Uniprot-TrEMBL)
p-5S,T404-IRF3	Protein	Q14653 (Uniprot-TrEMBL)
p-IRF3 p-IRF3	Complex	REACT_26064 (Reactome)
p-IRF3 dimer PIN1	Complex	REACT_26699 (Reactome)
p-S176,S180-CHUK	Protein	O15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB	Protein	O14920 (Uniprot-TrEMBL)
p-S477,S479-IRF7	Protein	Q92985 (Uniprot-TrEMBL)
p-S477,S479-IRF7	Protein	Q92985 (Uniprot-TrEMBL)
p-T,4S-IRF3 p-T,4S-IRF3	Complex	REACT_7146 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3	Complex	REACT_7444 (Reactome)
phosphorylated IRF3/IRF7	Protein	REACT_21760 (Reactome)
procaspase-8/10	Protein	REACT_26572 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	REACT_24935 (Reactome)
	ADP	Arrow	REACT_25327 (Reactome)
	ADP	Arrow	REACT_25368 (Reactome)
	ADP	Arrow	REACT_6848 (Reactome)
AGER ligands AGER		Arrow	REACT_6906 (Reactome)
ATP			REACT_24935 (Reactome)
ATP			REACT_25327 (Reactome)
ATP			REACT_25357 (Reactome)
ATP			REACT_25368 (Reactome)
ATP			REACT_6848 (Reactome)
	Activated IKK Complex	Arrow	REACT_24935 (Reactome)
Activated IKK Complex			REACT_6848 (Reactome)
	CASP10	Arrow	REACT_24999 (Reactome)
	CASP8	Arrow	REACT_24999 (Reactome)
CBP/p300			REACT_25099 (Reactome)
CBP/p300			REACT_25196 (Reactome)
CBP/p300			REACT_25275 (Reactome)
CYLD			REACT_25235 (Reactome)
	DAK	Arrow	REACT_25160 (Reactome)
	DDX58	Arrow	REACT_25235 (Reactome)
DDX58			REACT_25191 (Reactome)
DDX58			REACT_25357 (Reactome)
DHX58		TBar	REACT_25357 (Reactome)
	E2 enzyme	Arrow	REACT_25252 (Reactome)
FADD			REACT_25147 (Reactome)
IKK related kinases TBK1/IKK epsilon			REACT_25179 (Reactome)
IKKA IKKB NEMO			REACT_24935 (Reactome)
IKKA IKKB NEMO			REACT_25134 (Reactome)
IPS-1 ATG5-ATG12 conjugate			REACT_24982 (Reactome)
IPS-1 NLRX1		TBar	REACT_24957 (Reactome)
IRF1 Promotors of IFN alpha, IFN beta		Arrow	REACT_25209 (Reactome)
IRF2 promoters of INF alpha, INF beta		TBar	REACT_25209 (Reactome)
IRF3 bound to IFN-beta promoter		Arrow	REACT_25400 (Reactome)
	IRF3-P IRF7-P	Arrow	REACT_24983 (Reactome)
	IRF3-P IRF7-P	Arrow	REACT_25352 (Reactome)
IRF3-P IRF7-P			REACT_25196 (Reactome)
IRF3-P IRF7-P			REACT_25352 (Reactome)
IRF3-P dimer CBP/p300			REACT_25153 (Reactome)
IRF3/ IRF7			REACT_25170 (Reactome)
IRF7			REACT_25308 (Reactome)
ISG15 RIG-I conjugate		TBar	REACT_25357 (Reactome)
ISG15 UBEIL/UbcH8 CEB1			REACT_25191 (Reactome)
ISGylated IRF3		TBar	REACT_24932 (Reactome)
ITCH			REACT_25398 (Reactome)
IkBs NFkB			REACT_6848 (Reactome)
	K48polyUb RIG-I/MDA5	Arrow	REACT_25252 (Reactome)
	K48polyUb-TRAF3	Arrow	REACT_24974 (Reactome)
K48polyUb			REACT_24974 (Reactome)
K48polyUb			REACT_25398 (Reactome)
	K63-Ub	Arrow	REACT_25055 (Reactome)
K63polyUb-TRAF3			REACT_25364 (Reactome)
K63polyUb			REACT_25220 (Reactome)
MAP3K1			REACT_25003 (Reactome)
MAVS			REACT_24957 (Reactome)
MAVS			REACT_25223 (Reactome)
MDA5 DAK			REACT_25160 (Reactome)
	NFkB Complex	Arrow	REACT_6848 (Reactome)
NLRC5			REACT_25113 (Reactome)
NLRX1			REACT_25223 (Reactome)
OTUD5			REACT_25055 (Reactome)
PCBP2			REACT_24967 (Reactome)
PIN1			REACT_25077 (Reactome)
	Phospho-NF-kappaB Inhibitor	Arrow	REACT_6848 (Reactome)
Promoter region of type-I IFN genes			REACT_24975 (Reactome)
Promotor region of interferon beta			REACT_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 ligases			REACT_25220 (Reactome)
RIPK1			REACT_25147 (Reactome)
RNF125 E2 enzyme			REACT_25252 (Reactome)
	RNF125	Arrow	REACT_25252 (Reactome)
	SIKE1	Arrow	REACT_25051 (Reactome)
	SIKE1	Arrow	REACT_25079 (Reactome)
TANK			REACT_24986 (Reactome)
TAX1BP1 TNFAIP3			REACT_25179 (Reactome)
TBK1/IKKi SIKE1			REACT_25051 (Reactome)
TBK1/IKKi SIKE1			REACT_25079 (Reactome)
TRAF2 and TRAF6			REACT_25262 (Reactome)
	Ub	Arrow	REACT_25235 (Reactome)
VAF/pIRF7 CBP/p300 bound to type I IFN gene promoter		Arrow	REACT_25209 (Reactome)
VAF/pIRF7 CBP/p300			REACT_24975 (Reactome)
Viral dsRNA			REACT_25160 (Reactome)
Viral dsRNA			REACT_25357 (Reactome)
	dsRNA MDA5	Arrow	REACT_25160 (Reactome)
	dsRNA RIG-1/MDA5 IPS-1 TRAF3	Arrow	REACT_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	Arrow	REACT_25051 (Reactome)
	dsRNA RIG-1/MDA5 IPS-1 Ub-TRAF3 TBK1/IKKi	Arrow	REACT_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			REACT_24999 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 RIP-1/FADD			REACT_25167 (Reactome)
dsRNA RIG-I/MDA5 IPS-1 TRAF2/TRAF6 MEKK1			REACT_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	Arrow	REACT_25079 (Reactome)
	dsRNA RIG-I/MDA5 IPS-1 TRAF2/TRAF6 TANK TBK1/IKKi	Arrow	REACT_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	Arrow	REACT_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		TBar	REACT_24957 (Reactome)
	dsRNA RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD Casp-8/10 prodomain	Arrow	REACT_24999 (Reactome)
dsRNA RIG-I/MDA5 TRAF2/TRAF6 IPS-1 RIP-1/FADD Casp-8/10 prodomain			REACT_25134 (Reactome)
dsRNA RIG-I/MDA5			REACT_24957 (Reactome)
dsRNA RIG-I/MDA5			REACT_24982 (Reactome)
dsRNA RIG-I/MDA5			REACT_25113 (Reactome)
dsRNA bound to RIG-I			REACT_25220 (Reactome)
	p-2S-IRF7 p-2S-IRF7	Arrow	REACT_24983 (Reactome)
	p-2S-IRF7 p-2S-IRF7	Arrow	REACT_25352 (Reactome)
p-2S-IRF7 p-2S-IRF7			REACT_25099 (Reactome)
p-2S-IRF7 p-2S-IRF7			REACT_25352 (Reactome)
p-IRF3 p-IRF3			REACT_25077 (Reactome)
	p-S477,S479-IRF7	Arrow	REACT_25327 (Reactome)
	p-T,4S-IRF3 p-T,4S-IRF3	Arrow	REACT_24983 (Reactome)
	p-T,4S-IRF3 p-T,4S-IRF3	Arrow	REACT_25352 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3			REACT_25275 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3			REACT_25352 (Reactome)
	phosphorylated IRF3/IRF7	Arrow	REACT_25368 (Reactome)
procaspase-8/10			REACT_24946 (Reactome)
procaspase-8/10			REACT_25167 (Reactome)