SOCS3 Drives Proteasomal Degradation of TBK1 and Negatively Regulates Antiviral Innate Immunity----中国科学院微生物研究所

科研成果

论文题目:	SOCS3 Drives Proteasomal Degradation of TBK1 and Negatively Regulates Antiviral Innate Immunity
作者:	Liu Dong, Sheng Chunjie, Gao Shijuan, Yao Chen, Li Jiandong, Jiang Wei, Chen Huiming, Wu Jiaoxiang, Pan Changchuan, Chen Shuai, and Huang Wenlin.
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刊物名称:	Mol Cell Biol
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年份:	2015
影响因子:	5.614
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摘要:	TANK-binding kinase 1 (TBK1)-medicated induction of type I interferon plays critical role in host antiviral responses and immune homeostasis. The negative regulation of TBK1 activity is largely unknown. We report that suppressor of cytokine signaling 3 (SOCS3) inhibits IFN-beta signaling pathway by promoting proteasomal degradation of TBK1. Overexpression and knockdown experiments indicated that SOCS3 is a negative regulator of IRF3 phosphorylation and IFN-beta transcription. Moreover, SOCS3 directly associates with TBK1, and they co-localize in the cytoplasm. SOCS3 catalyzes K48-linked polyubiquitination of TBK1 at Lys341 and Lys344 and promotes subsequent TBK1 degradation. On the contrary, SOCS3 knockdown markedly increases the abundance of TBK1. Interestingly, both the BOX domain of SOCS3 and the Ser172 phosphorylation of TBK1 are indispensable for the process of ubiquitination and degradation. Ectopic expression of SOCS3 significantly inhibits vesicular stomatitis virus (VSV) and influenza A virus strain A/WSN/33 (WSN)-induced IRF3 phosphorylation and facilitates the replication of WSN virus by detecting the transcription of its vRNAs. Knockdown of SOCS3 represses WSN replication. Collectively, these results demonstrated that SOCS3 acts as a negative regulator of IFN-beta signal by ubiquitinating and degrading TBK1, which shed light on the understanding of antiviral innate immunity and provide potential target for developing antiviral agents.