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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.
AuthorsZhenzhen Zhan, Hao Cao, Xuefeng Xie, Linshan Yang, Peng Zhang, Yihan Chen, Huimin Fan, Zhongmin Liu, Xingguang Liu
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 8 Pg. 3849-57 (Oct 15 2015) ISSN: 1550-6606 [Electronic] United States
PMID26363053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 by The American Association of Immunologists, Inc.
Chemical References
  • Interferon Type I
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Phosphoprotein Phosphatases
  • protein phosphatase 4
Topics
  • Animals
  • Dendritic Cells (immunology, pathology)
  • Gene Expression Regulation (immunology)
  • Immunity, Innate
  • Interferon Type I (immunology)
  • Macrophages (immunology, pathology)
  • Mice
  • Phosphoprotein Phosphatases (immunology)
  • Phosphorylation (immunology)
  • Protein Serine-Threonine Kinases (immunology)
  • Respirovirus Infections (immunology, pathology)
  • Rhabdoviridae Infections (immunology, pathology)
  • Sendai virus (physiology)
  • Vesiculovirus (physiology)
  • Virus Replication (immunology)

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