蛋白质甲基化酶对RIG-I信号通路激活的调控机制研究

RIG-I signaling pathway is the major anti-viral pathway in cell. It recognizes the viral RNA and is regulated by multiple post translational modifications, such as phosphorylation and ubiquitination. WDR5 is one of the subunits of SET1A methyltransferase complex. WDR5 was reported to be involved in the activation of RIG-I signaling. After treated by virus, WDR5 is associated with VISA and translocated to mitochondria, where it regulates the phosphorylation and activation of IRF3. However, the molecular mechanisms of WDR5's function are yet not clear. Our preliminary data showed that not only WDR5, but also other subunits of SET1A complex, ASH2, RBBP5 and SET1A, are associated with VISA. This suggested that protein methylation mediated by SET1A complex might be involved in the regulation of RIG-I signaling. This project is planning to study the regulatory function of SET1A complex on RIG-I signaling pathway, screen new substrates of SET1A and discover the molecular mechanism. It is the first time to link protein methylation in cytoplasma with anti-viral signaling pathway, and will reveal the new research area in signaling transduction field.

RIG-I信号转导途径是细胞抗病毒反应的关键途径之一。该信号途径主要识别病毒的RNA，并受到磷酸化、泛素化等多种蛋白质翻译后修饰的调控。WDR5是SET1A组蛋白甲基化酶复合物的亚基之一，它参与了RIG-I信号途径。用病毒处理细胞后，WDR5与VISA相互作用，并定位在线粒体上，调控IRF3的磷酸化和激活。WDR5的调节作用的分子机制目前还不清楚。我们的初步实验结果发现，SET1A复合物中的其它亚基ASH2、RBBP5和SET1A都可以与VISA相互作用，提示SET1A介导的蛋白质的甲基化可能参与了RIG-I信号通路的调控。本项目计划研究SET1A复合物对RIG-I信号通路的调控作用，筛选SET1A的底物，揭示其分子机理。本项目将细胞质内蛋白质的甲基化与信号通路的调控相结合，将开辟信号转导途径研究的崭新领域。

RIG-I 信号转导途径是细胞抗病毒反应的关键途径之一。该信号途径主要识别病毒的RNA，并受到磷酸化、泛素化等多种蛋白质翻译后修饰的调控。WDR5 是SET1A 组蛋白甲基化酶复合物的亚基之一，它参与了RIG-I 信号途径的激活。在本项目的研究过程中，我们发现组蛋白H3K4甲基化酶的另外一个关键亚基，WDR82，通过与TRAF3相互作用，调节TRAF3的多聚泛素化，抑制SeV激活的RIG-I信号通路。本项目的研究成果说明H3K4甲基化酶复合物的多个亚基在多个层次参与调控抗病毒反应，其复杂调控机制值得深入研究。同时在本课题支持下，还完成了多个相关项目，说明了组蛋白甲基化酶MLL1在ER Stress中的作用，以及H3K27甲基化酶EZH1在调控NF-κB中的作用。目前项目负责人作为通讯作者发表了3篇研究论文和1篇综述，并有多篇文章在投稿或者写作中。