Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses
Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses
复制标题
Lck/Hck/Fgr 介导的酪氨酸磷酸化负向调节 TBK1 以抑制先天抗病毒反应
DOI：
10.1016/j.chom.2017.05.010
复制
发表时间：
2017-06-14
影响因子：
30.3
通讯作者：
Xu, Pinglong
中科院分区：
文献类型：
--
作者：
Liu, Shengduo;Chen, Shasha;Xu, Pinglong
胞质核酸传感通过蛋白质泛素化和 Ser/Thr 磷酸化控制的级联反应引发干扰素产生，以实现初级抗病毒防御。在这里，我们发现 TBK1（抗病毒途径的核心激酶）受到酪氨酸磷酸化的抑制。 Src 家族激酶 (SFK) Lck、Hck 和 Fgr 直接在 Tyr354/394 位点磷酸化 TBK1，以防止 TBK1 二聚化和激活。因此，Lck/Hck/Fgr 三重敲除细胞中的抗病毒感应和耐药性显着增强，而 Lck/Hck/Fgr 的异位表达削弱了细胞和斑马鱼的抗病毒防御。 SFK 的小分子抑制剂是传统的抗肿瘤疗法，可增强抗病毒反应并保护斑马鱼和小鼠免受病毒攻击。病毒感染通过TBK1介导的IRF3动员诱导Lck/Hck/Fgr的表达，从而构成负反馈环。这些发现揭示了 TBK1 通过酪氨酸磷酸化的负调节以及 SFK 与先天抗病毒免疫的功能整合。
Cytosolic nucleic acid sensing elicits interferon production for primary antiviral defense through cascades controlled by protein ubiquitination and Ser/Thr phosphorylation. Here we show that TBK1, a core kinase of antiviral pathways, is inhibited by tyrosine phosphorylation. The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. Accordingly, antiviral sensing and resistance were substantially enhanced in Lck/Hck/Fgr triple knockout cells and ectopic expression of Lck/Hck/Fgr dampened the antiviral defense in cells and zebrafish. Small-molecule inhibitors of SFKs, which are conventional anti-tumor therapeutics, enhanced antiviral responses and protected zebrafish and mice from viral attack. Viral infection induced the expression of Lck/Hck/Fgr through TBK1-mediated mobilization of IRF3, thus constituting a negative feedback loop. These findings unveil the negative regulation of TBK1 via tyrosine phosphorylation and the functional integration of SFKs into innate antiviral immunity.