ZCCHC3在抗病毒天然免疫识别及信号转导中的功能及作用机制

病毒感染后，宿主如何启动有效的抗病毒天然免疫以清除病毒是生物医学的一个热点问题。我们在前期工作中，发现锌指蛋白ZCCHC3在RNA病毒感染诱导下游抗病毒基因表达中发挥重要作用。ZCCHC3能够特异性地与胞质病毒RNA受体RIG-I和MDA5相互作用，并能够结合病毒RNA类似物。此外，ZCCHC3能够促进RIG-I和MDA5的K63链接的多聚泛素化。根据这些前期结果，我们提出的工作假说是ZCCHC3是RIG-I和MDA5识别病毒RNA并激活抗病毒天然免疫反应的一个辅助受体。本项目将利用分子细胞生物学、生物化学及病毒感染动物模型研究ZCCHC3在抗RNA病毒天然免疫信号转导中的功能和作用的分子机制。因为前期研究表明ZCCHC3在DNA病毒诱导下游基因表达中亦发挥重要作用，本项目还将阐释其在抗DNA病毒天然免疫信号转导中的功能机制。

How the host initiates efficient innate immune response after viral infection is a key question in the past years. In our preliminary studies, we found that the zinc finger protein ZCCHC3 is essential for RNA virus-triggered induction of downstream antiviral genes. ZCCHC3 interacted with RIG-I and MDA5, and could bind to viral RNA analog poly(I:C). In addition, ZCCHC3 also promoted K63-linked polyubiquitination of RIG-I and MDA5, which are hallmarks for their activation. Based on these results, we hypothesize that ZCCHC3 acts as a co-receptor for RIG-I and MDA5 in innate antiviral response to RNA virus. Since our preliminary studies also indicated that ZCCHC3 was involve in DNA virus-triggered induction of downstrean genes, this project will also investigate the mechanisms on how ZCCHC3 acts in innate immune response to DNA virus.