IRTKS抗病毒作用及其分子机制研究

IRTKS is an essential regulator downstream of the insulin receptor. It plays of great importance roles in various cellular events. Insulin resistance is always accompanied by pathogen infection. However, whether IRTKS is involved in pathogen infection is still elusive. During our study, we found that IRTKS knockout cells produced more type I interferons during RNA virus infection than control cells did and the replication of RNA viruses was inhibited in IRTKS deficient cells. Moreover, IRTKS knockout mice had an enhanced survival rate when challenged with RNA viruses and viral load in the organs of IRTKS deficient mice was also decreased. Moreover, we found that IRTKS acted on MAVS to inhibit the immune response against RNA viruses. In this project, we are going to verify the function of IRTKS in defensing RNA viruses using biochemical and molcular biological technologies, and finding out the mechanism on IRTKS in regulating virus infection.

IRTKS是胰岛素受体下游的重要调节因子，其缺失引起胰岛素耐受。胰岛素耐受与病原体易感性密切相关，但IRTKS与微生物感染的关系尚未阐明。我们发现IRTKS基因缺失的小鼠在RNA病毒感染的时候能够分泌更多的Ｉ型干扰素，小鼠在致死剂量RNA病毒感染时的生存率显著提高。还发现，IRTKS通过抑制RIG-I信号通路中RIG-I和MAVS等负反馈调节抗病毒反应，充分表明IRTKS是通过调控RIG-I-MAVS信号途径参与机体的抗病毒免疫应答反应。在此基础上，我们将以IRTKS基因缺失的小鼠为实验模型，研究在RNA病毒感染过程中IRTKS是如何通过MAVS发挥其负性调节作用的。同时，将研究IRTKS与RIG-I信号通路调节分子的相互作用网络，揭示IRTKS负反馈调节机体抗病毒反应的分子机制，从而加深我们对机体抵御病毒感染的免疫调节稳态的认识。

RNA病毒感染是由RIG-I受体家族介导识别的，它能激活线粒体适配器mavs，从而达到清除病毒的目的。抗病毒信号激活需要严格的调节，以避免因炎症加剧而对宿主造成损害。胰岛素受体酪氨酸激酶底物（IRTKS）参与肌动蛋白结合和胰岛素信号传导，其缺失会导致胰岛素抵抗的产生。然而，IRTKS是否参与天然免疫的调节仍然不清楚。在这里，我们发现IRTKS缺乏会导致对RNA病毒的固有免疫反应增强。IRTKS介导的对抗病毒反应的抑制作用依赖于RIG-I-MAVS信号通路。IRTKS将E2连接酶Ubc9募集到细胞核中的苏木化的PCBP2上，在病毒感染时引起胞质易位。苏木化的 PCBP2与MAVS相互作用启动MAVS的降解，导致抗病毒反应的下调。因此，IRTKS是过度炎症的负调节因子。