title: Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1.
abstract: The effective recognition of viral infection and subsequent type I IFN production is essential for the host antiviral innate immune responses. The phosphorylation and activation of kinase TANK-binding kinase 1 (TBK1) plays crucial roles in the production of type I IFN mediated by TLR and retinoic acid-inducible gene I-like receptors. Type I IFN expression must be tightly regulated to prevent the development of immunopathological disorders. However, how the activated TBK1 is negatively regulated by phosphatases remains poorly understood. In this study, we identified a previously unknown role of protein phosphatase (PP)4 by acting as a TBK1 phosphatase. PP4 expression was upregulated in macrophages infected with RNA virus, vesicular stomatitis virus, and Sendai virus in vitro and in vivo. Knockdown of PP4C, the catalytic subunit of PP4, significantly increased type I IFN production in macrophages and dentritic cells triggered by TLR3/4 ligands, vesicular stomatitis virus, and Sendai virus, and thus inhibited virus replication. Similar results were also found in peritoneal macrophages with PP4C silencing in vivo and i.p. infection of RNA virus. Accordingly, ectopic expression of PP4C inhibited virus-induced type I IFN production and promoted virus replication. However, overexpression of a phosphatase-dead PP4C mutant abolished the inhibitory effects of wild-type PP4C on type I IFN production. Mechanistically, PP4 directly bound TBK1 upon virus infection, then dephosphorylated TBK1 at Ser(172) and inhibited TBK1 activation, and subsequently restrained IFN regulatory factor 3 activation, resulting in suppressed production of type I IFN and IFN-stimulated genes. Thus, serine/threonine phosphatase PP4 functions as a novel feedback negative regulator of RNA virus-triggered innate immunity.
authors.affiliation: Research Center for Translational Medicine and Shanghai Heart Failure Research Center, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; liuxg@immunol.org zhanzz@tongji.edu.cn.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhan
authors.affiliation: Research Center for Translational Medicine and Shanghai Heart Failure Research Center, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
authors.forename: Hao
authors.initials: H
authors.lastname: Cao
authors.affiliation: School of Pharmacology, Anhui Medical University, Hefei 230032, China; and.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Xie
authors.affiliation: Research Center for Translational Medicine and Shanghai Heart Failure Research Center, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
authors.forename: Linshan
authors.initials: L
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Research Center for Translational Medicine and Shanghai Heart Failure Research Center, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
authors.forename: Yihan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Research Center for Translational Medicine and Shanghai Heart Failure Research Center, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
authors.forename: Huimin
authors.initials: H
authors.lastname: Fan
authors.affiliation: Research Center for Translational Medicine and Shanghai Heart Failure Research Center, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China liuxg@immunol.org zhanzz@tongji.edu.cn.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology*; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D010253:Respirovirus Infections / Q000276:immunology* / Q000473:pathology; D018353:Rhabdoviridae Infections / Q000276:immunology* / Q000473:pathology; D029082:Sendai virus / Q000502:physiology*; D018116:Vesiculovirus / Q000502:physiology*; D014779:Virus Replication / Q000276:immunology*
chemical_list: D007370:Interferon Type I; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4