title: PIAS1 negatively modulates virus triggered type I IFN signaling by blocking the DNA binding activity of IRF3.
abstract: During viral infection, production of proinflammatory cytokines including type I interferons (IFNs) is under stringent control to avoid detrimental overreaction. The protein inhibitor of activated STAT (PIAS) family proteins have been recognized as anti-inflammatory molecules by restraining type I IFN induced amplifying signaling. Here we identified PIAS1 as an important negative regulator of virus-triggered type I IFN signaling. Overexpression of PIAS1 repressed virus-or RIG-I like receptor stimulated type I IFN transcription, whereas knockdown of PIAS1 expression augmented virus-induced production of type I IFNs. PIAS1 with a mutation in the SAP domain retained the inhibitory function in virus-induced IFN transcription, but abolished the inhibition in IFN-stimulated signaling. SUMO E3 ligase activity dead mutant PIAS1/C350S still had the comparable inhibitory function with WT PIAS1. Further study indicated that PIAS1 interacted with IRF3 and inhibited the DNA binding activity of IRF3. The C-terminal region of PIAS1 around a cluster of acidic amino acids is critical for the interaction with IRF3 and the inhibitory functions of PIAS1. Therefore, these results unveil PIAS1 functions both at the virus-induced early signaling stage and IFN stimulated amplifying stage with distinct mechanisms. PIAS1 is important in maintaining proper amounts of type I IFNs and restrains its magnitude when the antiviral response intensifies.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology (Ministry of Health), Peking University Health Science Center, Beijing 100191, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Pan
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Shi
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors*; D007370:Interferon Type I / Q000096:biosynthesis*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D025941:Protein Interaction Mapping; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D050505:Mutant Proteins; C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins; D004247:DNA
keywords: IRF3; Interferon; PIAS1; SUMOylation; Transcription