SOCS3 Drives Proteasomal Degradation of TBK1 and Negatively Regulates Antiviral Innate Immunity
SOCS3 Drives Proteasomal Degradation of TBK1 and Negatively Regulates Antiviral Innate Immunity
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DOI：
10.1128/mcb.00090-15
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发表时间：
2015-07-01
影响因子：
5.3
通讯作者：
Huang, Wenlin
中科院分区：
文献类型：
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作者：
Liu, Dong;Sheng, Chunjie;Huang, Wenlin
TANK结合激酶1（TBK 1）介导的I型干扰素（IFN）诱导在宿主抗病毒应答和免疫稳态中起关键作用。TBK 1活性的负调控在很大程度上是未知的。我们报道了细胞因子信号抑制因子3（SOCS 3）通过促进TBK 1的蛋白酶体降解来抑制IFN-β信号通路。过表达和敲低实验表明，SOCS 3是IFN调节因子3（IRF 3）磷酸化和IFN-β转录的负调节因子。此外，SOCS 3与TBK 1直接相关，并且它们共定位于细胞质中。SOCS 3催化TBK 1在Lys 341和Lys 344处的K48连接的多泛素化，并促进随后的TBK 1降解。相反，SOCS 3敲除显著增加了TBK 1的丰度。有趣的是，SOCS 3的BOX结构域和TBK 1的Ser 172磷酸化对于泛素化和降解过程都是不可或缺的。SOCS 3的异位表达显著抑制水泡性口炎病毒（VSV）和甲型流感病毒株A/WSN/33（WSN）诱导的IRF 3磷酸化，并通过检测其病毒RNA（vRNA）的转录促进WSN病毒的复制。SOCS 3的敲除抑制了WSN的复制。总的来说，这些结果表明，SOCS 3通过泛素化和降解TBK 1作为IFN-β信号的负调节剂，揭示了抗病毒先天免疫的理解，并为开发抗病毒药物提供了潜在的靶点。
TANK-binding kinase 1 (TBK1)-mediated induction of type I interferon (IFN) plays a 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 the IFN-beta signaling pathway by promoting proteasomal degradation of TBK1. Overexpression and knockdown experiments indicated that SOCS3 is a negative regulator of IFN regulatory factor 3 (IRF3) phosphorylation and IFN-beta transcription. Moreover, SOCS3 directly associates with TBK1, and they colocalize 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 Ser172 phosphorylation of TBK1 are indispensable for the processes 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 viral RNA (vRNA). Knockdown of SOCS3 represses WSN replication. Collectively, these results demonstrate that SOCS3 acts as a negative regulator of IFN-beta signal by ubiquitinating and degrading TBK1, shed light on the understanding of antiviral innate immunity, and provide a potential target for developing antiviral agents.