病毒DNA被细胞浆内的cGas所识别，通过接头蛋白MITA激活下游信号转导并诱导抗病毒蛋白表达。我们在前期研究中发现Trim38在DNA病毒感染前后动态的催化cGas和Mita的SUMO化并在抗DNA病毒天然免疫信号转导中发挥关键作用。本项目的科学问题是：抗DNA病毒天然免疫是如何受到SUMO化和其它类型的蛋白翻译后修饰在时空上协调地调控，以确保在病毒感染早期有效地启动而在晚期及时的终止？为此，本项目主要研究内容包括：1) 鉴定病毒感染前后cGas和Mita的SUMO化位点，确定不同位点SUMO化在抗病毒天然免疫中的功能；2）探索cGas和Mita的SUMO化与其他翻译后修饰如泛素化和磷酸化等在时空上的动态调节关系；3）阐述cGas和Mita的去SUMO化和降解机制。本项目的成功完成有助于揭示抗DNA病毒天然免疫信号转导的精细分子调控机制，并为研发感染与自身免疫疾病和癌症药物提供分子靶标。

Viral DNA is recognized by the cGAMP synthase cGas, which initiates innate immune response to DNA virus. Mita is an adaptor protein critically involved in cGas-mediated induction of downstream antiviral genes. How the cGas-Mita pathway is optimally activated at the early phase of viral infection to establish efficient innate immune response and then timely turned off at the late phase to avoid excessive immune damage is enigmatic. In our preliminary study, we found that Trim38 was required for innate immune response to viral and cytosolic DNA. Trim38 acted as a SUMO E3 ligase, which targeted cGas and Mita for sumoylation in un-infected or early-infected cells respectively. The specific aims of this project include: 1) To determine the sumoylation residues and cGas and Mita, and the effects of the sumoylation on innate immune signaling triggered viral DNA; 2) To investigate the spatial and temporal relationships between sumoylation of cGas/Mita and their other types of post-translational modifications such as polyubiquitination and phosphorylation; 3) To identify the enzyme(s) responsible for the desumoylation of cGas/Mita as well as the mechanisms of degradation of cGas/Mita at the late phase of viral infection. The successful completion of this project will only only provide a comprehensive understanding on the delicate regulatory mechanisms that ensure proper innate immune response to DNA virus, but also provide potential targets for drug development against infectious and autoimmune diseases and cancer.