DDOST在抗病毒天然免疫中的作用及其分子机制

入侵宿主的病毒释放核酸，会被宿主细胞内核酸感受器识别，导致下游接头蛋白及信号通路的活化，诱导转录因子IRF3、NF-kappaB和STAT6活化入核，启动抗病毒I型干扰素、炎症因子及趋化因子的表达。这些抗病毒信号转导通路受到多种层次的精密调控。在前期研究中我们发现DDOST参与抗病毒天然免疫I型干扰素产生的信号转导调控，敲低DDOST的表达能显著抑制DNA病毒和RNA病毒诱导的I型干扰素表达，DDOST也与STING具有相互作用，但具体作用机制尚不清楚。我们据此提出科学假说：DDOST可能通过作用于STING，促进STING的转位和翻译后修饰，从而推动抗DNA病毒天然免疫反应的进程。我们将构建Ddost敲除人源细胞和条件敲除小鼠，通过体外和在体实验，探索DDOST在抗DNA和/或RNA病毒天然免疫调控中的作用及其分子机制。本研究将为相关感染性疾病的防治提供新的分子靶标及理论依据。

Anti-viral innate immune responses start from the recognition of viral nucleic acid by DNA sensors or RNA sensors. The activated sensors passage the signal to the downstream adaptors, and lead to the activation of transcription factor IRF3, NF-kappaB and STAT6, which initiate the transcription of antiviral type I interferon, inflammation cytokines and chemokines. These signal pathway should be precisely regulated to ensure the proper immune responses. Recently, we found a multifunctional protein named DDOST participates in the signal pathway leading to type I IFN production. Knockdown of DDOST inhibits the expression of IFNs induced by both DNA and RNA viruses. We also found the interaction between DDOST and STING. But the detail mechanism of its function is still unclear. In the present project, we plan to examine the molecular mechanism of DDOST in antiviral STING and MAVS pathways through in vitro and in vivo experiments using gene-knockout cells and mouse. This project will provide new target and evidence for prevention and therapy of relative infectious diseases.