MITA的N-聚糖修饰在抗DNA病毒天然免疫中的作用和机制研究

过去十年，病毒RNA诱导细胞抗病毒天然免疫分子机制的研究已取得很大进展。然而，随着cGAS和cGAMP的发现，病毒DNA诱导细胞抗病毒天然免疫分子机制才开始被逐步了解。MITA是cGAS和cGAMP下游的关键接头蛋白，它对于抗DNA病毒天然免疫反应的激活至关重要。因此，MITA的活性被宿主免疫系统严格调控。目前的研究表明，MITA的活性能被泛素化、磷酸化等修饰调控，但是MITA其它的翻译后修饰还了解得很少。申请人前期的研究显示MITA具备潜在的N-聚糖修饰位点，且该位点突变能显著的影响DNA病毒和胞内DNA诱导的下游抗病毒基因的表达。通过本项研究，我们将回答两个关键科学问题：1)MITA的N-聚糖修饰在抗DNA病毒天然免疫反应中的作用；2)N-聚糖修饰调控MITA活性及其下游信号转导的分子机制。本研究有望揭示N-聚修饰与MITA介导的天然免疫的关系，并有助于深入理解MITA活化的动态调控。

Studies during the past decade have led to considerable advances in the mechanisms of viral RNA-triggered innate immune signaling. However, with the discovery of cGAS and cGAMP, the mechanisms of viral DNA-triggered innate immune signaling are emerging in recent years. MITA, acts as a critical downstream adaptor of cGAS and cGAMP, is essential for the activation of innate immune response to DNA virus. Hence, MITA is rigorously regulated by host immune system. Current studies demonstrate that the activity of MITA is regulated by various modifications such as ubiquitylation and phosphorylation, but little is known about other types of posttranslational modification of MITA. Current works by applicant show that MITA possesses two potential N-glycan modification sites, and mutants of N-glycan modification site lead to significant effect on the expression of downstream antiviral genes induced by DNA virus and intracellular DNA. We will answer two key scientific problems with accomplishment of this project: 1) what is the role of N-glycan modification of MITA in innate immune response to DNA virus; 2) what are the mechanisms of MITA activation and MITA-medicated downstream signal transduction regulated by N-glycan modification. This work may reveal an unknown links between N-glycan modification and MITA-mediated signaling, and provide valuable insights into the dynamic regulatory mechanisms for MITA activation.