title: WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines.
abstract: Upon virus infection, retinoic acid-inducible gene I-like receptors in host cells recognize viral RNA and activate type I IFN expression. Previously, we identified WD repeat domain (WDR) 5 as one positive regulator for pathway activation. In this study, we report that WDR82, a homolog protein of WDR5, acts opposite to WDR5 and inhibits the activation of the retinoic acid-inducible gene I signaling pathway. WDR82 overexpression inhibits virus-triggered pathway activation, whereas its knockdown enhances induced IFN-β expression. WDR82 is localized on the mitochondria, and its first N-terminal WD40 domain is critical for localization. WDR82 interacts with TNFR-associated factor (TRAF) 3, and its overexpression promotes K48-linked, but not K63-linked, polyubiquitination on TRAF3. Furthermore, WDR82 knockdown inhibits viral replication in the cell, whereas its overexpression has the opposite effect. Interestingly, WDR82 regulates Sendai virus-induced IFNB1 expression in a cell type-specific manner. Taken together, our findings demonstrate that WDR82 is a negative regulator of virus-triggered type I IFNs pathway through mediating TRAF3 polyubiquitination status and stability on mitochondria.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors.forename: Lin-Gao
authors.initials: LG
authors.lastname: Ju
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China.
authors.forename: Yanyi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and lilianyun@whu.edu.cn wumin@whu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and lilianyun@whu.edu.cn wumin@whu.edu.cn.
authors.forename: Lian-Yun
authors.identifier: http://orcid.org/0000-0003-4194-3059
authors.initials: LY
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D005347:Fibroblasts; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D012367:RNA, Viral / Q000276:immunology; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D054875:Ubiquitination; D054243:Vesicular Stomatitis / Q000276:immunology / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D012367:RNA, Viral; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; C534139:WDR82 protein, human; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases