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题名: TanK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Type I Interferon Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation
作者: Hu, Yi Wei1, 2; Zhang, Jie1; Wu, Xiao Man1; Cao, Lu1; Nie, Pin1, 3; Chang, Ming Xian1, 3
关键词: alternative splicing ; spring viremia of carp virus ; TANK-binding kinase 1 spliced isoforms ; TANK-binding kinase 1 ; IRF3 ; type I interferon signaling ; immune homeostasis
刊名: FRONTIERS IN IMMUNOLOGY
发表日期: 2018-01-30
DOI: 10.3389/fimmu.2018.00084
卷: 9
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ; Life Sciences & Biomedicine
类目[WOS]: Immunology
研究领域[WOS]: Immunology
英文摘要: TANK-binding kinase 1 (TBK1) is an important serine/threonine-protein kinase that mediates phosphorylation and nuclear translocation of IRF3, which contributes to induction of type I interferons (IFNs) in the innate antiviral response. In mammals, TBK1 spliced isoform negatively regulates the virus-triggered IFN-beta signaling pathway by disrupting the interaction between retinoic acid-inducible gene I (RIG-I) and mitochondria antiviral-signaling protein (MAVS). However, it is still unclear whether alternative splicing patterns and the function of TBK1 isoform(s) exist in teleost fish. In this study, we identify two alternatively spliced isoforms of TBK1 from zebrafish, termed TBK1_tv1 and TBK1_tv2. Both TBK1_tv1 and TBK1_tv2 contain an incomplete STKc_TBK1 domain. Moreover, the UBL_TBK1_like domain is also missing for TBK1_tv2. TBK1_tv1 and TBK1_tv2 are expressed in zebrafish larvae. Overexpression of TBK1_tv1 and TBK1_tv2 inhibits RIG-I-, MAVS-, TBK1-, and IRF3-mediated activation of IFN promoters in response to spring viremia of carp virus infection. Also, TBK1_tv1 and TBK1_tv2 inhibit expression of IFNs and IFN-stimulated genes induced by MAVS and TBK1. Mechanistically, TBK1_tv1 and TBK1_tv2 competitively associate with TBK1 and IRF3 to disrupt the formation of a functional TBK1-IRF3 complex, impeding the phosphorylation of IRF3 mediated by TBK1. Collectively, these results demonstrate that TBK1 spliced isoforms are dominant negative regulators in the RIG-I/MAVS/TBK1/IRF3 antiviral pathway by targeting the functional TBK1-IRF3 complex formation. Identification and functional characterization of piscine TBK1 spliced isoforms may contribute to understanding the role of TBK1 expression in innate antiviral response.
关键词[WOS]: PATTERN-RECOGNITION RECEPTORS ; MAVS SPLICING VARIANTS ; IFN-BETA PRODUCTION ; ANTIVIRAL RESPONSE ; RIG-I ; FUNCTIONAL-CHARACTERIZATION ; STIMULATED GENES ; IKK-EPSILON ; PROTEIN ; EXPRESSION
语种: 英语
项目资助者: National Natural Science Foundation of China(31372531 ; 31672687)
WOS记录号: WOS:000423556800001
ISSN号: 1664-3224
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内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/342005/50648
Appears in Collections:鱼类生物学及渔业生物技术研究中心_期刊论文

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作者单位: 1.Chinese Acad Sci, Inst Hydrobiol, State Key Lab Freshwater Ecol & Biotechnol, Wuhan, Hubei, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Minist Agr, Key Lab Aquaculture Dis Control, Wuhan, Hubei, Peoples R China
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