title: FoxO1 negatively regulates cellular antiviral response by promoting degradation of IRF3.
abstract: Viral infection causes activation of the transcription factor IRF3, which is critical for production of type I interferons (IFNs) and innate antiviral immune response. How virus-induced type I IFN signaling is controlled is not fully understood. Here we identified the transcription factor FoxO1 as a negative regulator for virus-triggered IFN-β induction. Overexpression of FoxO1 inhibited virus-triggered ISRE activation, IFN-β induction as well as cellular antiviral response, whereas knockdown of FoxO1 had opposite effects. FoxO1 interacted with IRF3 in a viral infection-dependent manner and promoted K48-linked polyubiquitination and degradation of IRF3 in the cytosol. Furthermore, FoxO1-mediated degradation of IRF3 was independent of the known E3 ubiquitin ligases for IRF3, including RBCK1 and RAUL. Our findings thus suggest that FoxO1 negatively regulates cellular antiviral response by promoting IRF3 ubiquitination and degradation, providing a previously unknown mechanism for control of type I IFN induction and cellular antiviral response.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Cao-Qi
authors.initials: CQ
authors.lastname: Lei
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.forename: Li-Qun
authors.initials: LQ
authors.lastname: Jiang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D000818:Animals; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D059748:Proteolysis; D018353:Rhabdoviridae Infections / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D018116:Vesiculovirus / Q000235:genetics / Q000378:metabolism*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D014157:Transcription Factors; D016899:Interferon-beta; C555759:UBE3C protein, human; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Innate Immunity; Interferon; Signal Transduction; Ubiquitination; Virus