抗DNA病毒天然免疫信号转导的翻译后修饰调节

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.

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。

病毒感染通过激活转录因子NF-kB和IRF3诱导I型干扰素和促炎症因子的表达。本项目在我们前期工作的基础上，进一步探索了病毒感染诱导I 型干扰素表达的分子机制。我们在项目执行期间，发现了多个参与调控抗病毒天然免疫的信号蛋白，并揭示了相关分子机制，在国际上产生了重要的影响。发表SCI论文37篇，包括1篇Immunity，1篇Cell Host & Microbe，1篇Cell Research，5篇PNAS，4篇Nature Communications，1篇JEM等；培养硕士和博士研究生19名；3人获得博士后创新人才支持计划。