title: TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS.
abstract: Upon virus infection, host cells use retinoic-acid-inducible geneI I (RIG-I)-like receptors to recognize viral RNA and activate type I IFN expression. To investigate the role of protein methylation in the antiviral signaling pathway, we screened all the SET domain-containing proteins and identified TTLL12 as a negative regulator of RIG-I signaling. TTLL12 contains SET and TTL domains, which are predicted to have lysine methyltransferase and tubulin tyrosine ligase activities, respectively. Exogenous expression of TTLL12 represses IFN-β expression induced by Sendai virus. TTLL12 deficiency by RNA interference and CRISPR-gRNA techniques increases the induced IFN-β expression and inhibits virus replication in the cell. The global gene expression profiling indicated that TTLL12 specifically inhibits the expression of the downstream genes of innate immunity pathways. Cell fractionation and fluorescent staining indicated that TTLL12 is localized in the cytosol. The mutagenesis study suggested that TTLL12's ability to repress the RIG-I pathway is probably not dependent on protein modifications. Instead, TTLL12 directly interacts with virus-induced signaling adaptor (VISA), TBK1, and IKKε, and inhibits the interactions of VISA with other signaling molecules. Taken together, our findings demonstrate TTLL12 as a negative regulator of RNA-virus-induced type I IFN expression by inhibiting the interaction of VISA with other proteins.
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Lin-Gao
authors.initials: LG
authors.lastname: Ju
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Pin-Ji
authors.initials: PJ
authors.lastname: Lei
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yan
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Qing-Lan
authors.initials: QL
authors.lastname: Li
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Xue-Jing
authors.initials: XJ
authors.lastname: Li
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Jian-Wen
authors.identifier: 0000-0002-4438-7898
authors.initials: JW
authors.lastname: Chen
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China lilianyun@whu.edu.cn wumin@whu.edu.cn.
authors.forename: Lian-Yun
authors.identifier: 0000-0003-4194-3059
authors.initials: LY
authors.lastname: Li
authors.affiliation: Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China lilianyun@whu.edu.cn wumin@whu.edu.cn.
authors.forename: Min
authors.identifier: 0000-0003-1372-4764
authors.initials: M
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D002352:Carrier Proteins / Q000032:analysis / Q000502:physiology*; D002460:Cell Line; D003600:Cytosol / Q000737:chemistry; D000071457:DEAD Box Protein 58 / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D007113:Immunity, Innate; D007370:Interferon Type I / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007370:Interferon Type I; C505371:MAVS protein, human; D011971:Receptors, Immunologic; C551992:TTLL10 protein, human; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58