代谢酶IRG1调控免疫细胞代谢状态抑制病毒复制的分子机制研究

Metabolism is likely to play a key role in the mechanism of antivirus and the immune escape mechanism of the virus. In this project, we found that the immune enzyme gene 1 (IRG1) can interact with MAVS and the expression of IRG1 increased significantly after viral stimulation. Further studies have found that IRG1 can inhibit viral replication and significantly positively regulate the production of virus-induced type I interferon. Therefore, it is presumed that IRG1 may affect the natural response to antiviral and immune cells by affecting the functional status of MAVS or by remodeling the metabolic state of cells. This project will explore the biological mechanisms of its positive regulation of antiviral innate immunity and will obtain the evidence of the transcriptome and metabolome metabolism changes for IRG1 deletion. We will focus on the most important metabolic pathways to explore its mechanisms. We will also excavate its value in clinical applications through the collection and analysis of the related clinical samples. The completion of this project will provide new targets and new ideas for the prevention and control methods of viral infection, which has theoretical significance and potential application value.

代谢在机体抗病毒机制以及病毒的免疫逃逸机制中很可能会发挥关键作用。本课题组在对抗病毒天然免疫明星分子MAVS相互作用蛋白分析中意外发现，代谢酶免疫应答基因1(IRG1)蛋白与MAVS相互结合，且在病毒刺激后表达显著升高。进一步研究发现IRG1能抑制病毒复制，显著正向调节病毒诱导的I型干扰素产生。由此推测IRG1很可能通过影响MAVS的功能状态或通过重塑细胞代谢状态，影响抗病毒天然应答及免疫细胞抗病毒。本课题拟通过已构建的敲除小鼠等探究其正向调控抗病毒天然免疫的生物学机制；通过转录组和代谢组高通量组学分析寻找IRG1缺失之后细胞代谢状态改变的证据，并聚焦其中最为重要的代谢通路；通过质谱、免疫共沉淀等筛选IRG1的相互作用蛋白及其相互作用方式；通过对相关临床样本的采集和分析，挖掘其在临床应用中的价值。本课题的完成可为病毒性感染防治方法的研发提供新的靶点和新的思路，具有理论意义和潜在的应用价值。

IRG1-衣康酸广泛参与调控机体炎症反应和抵抗细菌感染，但其对病毒复制的效应和机制尚不完全清楚。本课题发现IRG1-衣康酸可以促进病毒复制，且不依赖I型干扰素途径。机制上我们发现衣康酸促进异戊烯化转移酶GGTase-II介导的蛋白膜转位活动，继而促进病毒复制。GGTase-II主要调控Rab家族分子的膜转位活动，这些分子广泛参与病毒复制的各个环节。衣康酸可以显著增加Rab5、Rab7和Rab11在细胞膜上的定位。干扰GGTase-II及下游靶蛋白Rab5、Rab7、Rab11都可有效减弱衣康酸对病毒复制的作用。综上，衣康酸通过促进GGTaseII介导的蛋白膜转位促进病毒复制。本课题研究成果在SCI杂志发表相关论文4篇（其中1篇影响因子高于10分，2篇高于5分），另有一篇正在整理准备文稿中。课题负责人获评上海市领军人才（2019），培养研究生5名，其中1名博士和1名硕士已顺利毕业。本课题的完成将为临床抗病毒治疗提供新的潜在靶点和治疗策略。