title: A20 is a negative regulator of IFN regulatory factor 3 signaling.
abstract: IFN regulatory factor 3 (IRF-3) is a critical transcription factor that regulates an establishment of innate immune status following detection of viral pathogens. Recent studies have revealed that two IkappaB kinase (IKK)-like kinases, NF-kappaB-activating kinase/Traf family member-associated NF-kappaB activator-binding kinase 1 and IKK-i/IKKepsilon, are responsible for activation of IRF-3, but the regulatory mechanism of the IRF-3 signaling pathway has not been fully understood. In this study, we report that IRF-3 activation is suppressed by A20, which was initially identified as an inhibitor of apoptosis and inducibly expressed by dsRNA. A20 physically interacts with NF-kappaB-activating kinase/Traf family member-associated NF-kappaB activator-binding kinase 1 and IKK-i/IKKepsilon, and inhibits dimerization of IRF-3 following engagement of TLR3 by dsRNA or Newcastle disease virus infection, leading to suppression of the IFN stimulation response element- and IFN-beta promoter-dependent transcription. Importantly, knocking down of A20 expression by RNA interference results in enhanced IRF-3-dependent transcription triggered by the stimulation of TLR3 or virus infection. Our study thus demonstrates that A20 is a candidate negative regulator of the signaling cascade to IRF-3 activation in the innate antiviral response.
authors.affiliation: Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyagishi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Taira
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D019281:Dimerization; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D009522:Newcastle disease virus / Q000276:immunology; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3