KSHV逃逸宿主天然免疫信号通路cGAS-STING的结构基础与作用机制研究

cGAS-STING介导的I型干扰素信号通路是宿主识别DNA病毒感染的一种重要的天然免疫系统，病毒在与宿主免疫系统共同进化的压力下也发展出了多种通过抑制STING或cGAS活性来逃逸宿主免疫系统的策略。卡波氏肉瘤相关疱疹病毒 (KSHV) 主要通过潜伏相关核抗原LANA、干扰素调节因子vIRF1和衣壳蛋白ORF52等与STING或cGAS的直接相互作用来逃逸该通路，但目前对这一过程的分子机制还缺乏深入研究。本课题将解析KSHV的这些靶标蛋白与STING或cGAS复合物的晶体结构和溶液构象并进行比较。在此基础上通过蛋白定点突变和核酸酶活性测定等方法深入研究这些蛋白在体内和体外的相互作用以及对该信号通路中其它蛋白生理活性的影响。研究结果将在分子水平上揭示这些蛋白识别并抑制STING或cGAS活性，从而拮抗宿主免疫系统和抑制免疫应答的分子机制，为开发治疗KSHV感染的新型抗病毒药物提供重要参考。

The cGAS (cyclic GMP-AMP synthase) and STING (stimulator of interferon genes) are important mediators of the innate immune response to DNA viruses. Activation of this pathway leads to the production of type I interferon (IFN-1) and a subsequent antiviral response. Meanwhile, the viruses have developed counter-strategies to subvert host cGAS-STING signaling pathway in order to evade the innate immune response during their co-evolution. Kaposi’s sarcoma-associated herpesvirus (KSHV) infection can activate the cGAS-STING pathway, and cGAS and STING play an important role in regulating KSHV reactivation from latency. KSHV encoding latency-associated nuclear antigen (LANA), vIRF1 (viral interferon regulatory factor 1) and tegument protein ORF52 can inhibit the pathway by their direct interactions with cGAS or STING. In this project, we aim to solve the crystal structures and solution conformations of LANA, vIRF1 and ORF52 in complex with cGAS or STING by protein crystallography and small-angle X-ray scattering (SAXS). On this basis, we are going to perform the in vivo and in vitro interaction studies between these viral proteins and cGAS/STING by site-directed mutagenesis and the resulting effects on host physiological processes. The results will reveal the molecular mechanisms of cGAS/STING recognition by these viral proteins, and subsequent inhibition of IFN production by KSHV. Our findings will provide new insights into the host-virus interaction and help to develop novel antiviral approaches for the treatment of KSHV infection.