title: Cytoplasmic STAT4 Promotes Antiviral Type I IFN Production by Blocking CHIP-Mediated Degradation of RIG-I.
abstract: Retinoic acid-inducible gene I (RIG-I) signaling is critical to host innate immune response against RNA virus infection. Numerous factors use different mechanisms to regulate RIG-I signaling. In this study, we report that STAT family member STAT4 promotes RIG-I-triggered type I IFN production in antiviral innate immunity. Silencing of STAT4 impaired IFN-β production in macrophages upon RNA virus infection, whereas overexpression of STAT4 enhanced RIG-I-induced IFN-β promoter activation and IFN-stimulated response element activity. Silencing of STAT4 increased degradation of RIG-I. Interestingly, during RNA virus infection STAT4 was found to be constantly present in cytoplasm of macrophages without Tyr(693) phosphorylation, which is required for its classical activation and nuclear translocation. Mechanistically, cytoplasmic STAT4 could interact with E3 ligase CHIP and block RIG-I and CHIP association, preventing CHIP-mediated proteasomal degradation of RIG-I via K48-linked ubiquitination. Our study provides a new manner for posttranslational regulation of RIG-I signaling and identifies a previously unknown function of cytoplasm-localized STAT4 in antiviral innate immunity.
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China; and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors.forename: Dezhi
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China; and.
authors.forename: Qicong
authors.initials: Q
authors.lastname: Shen
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Mingjin
authors.initials: M
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China; and.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China; and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China caoxt@immunol.org.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D012327:RNA Virus Infections / Q000276:immunology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D034741:RNA, Small Interfering; D050797:STAT4 Transcription Factor; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases