去泛素化酶USP39对I型干扰素抗病毒效应的调控作用及其机制研究

干扰素 (Interferon,IFN) 是机体抵抗外界病毒感染最重要的细胞因子。IFN通过激活下游一系列干扰素刺激基因的转录和表达，最终发挥其抗病毒效应，而STAT1蛋白水平对于维持IFN通路活性至关重要。泛素化修饰在疾病相关的信号传导中扮演着重要角色，精细调控着蛋白水平和信号通路。我们前期大规模筛选去泛素化酶(DUBs)siRNA工作中，首次发现USP39具有抗病毒效应。实验初步证明，USP39能够减少STAT1蛋白的泛素化水平，维持STAT1蛋白的稳定性，从而增强IFN下游信号通路活性。本研究拟采用基因过表达和siRNA干扰技术、荧光标记显微技术、免疫共沉淀等多种技术手段，进一步探讨USP39和STAT1的相互作用和泛素化调控，并深入研究USP39对IFN信号通路及其抗病毒功能影响。项目开展将为IFN信号通路调控机制研究提供全新视角，也有望为我们临床提高抗病毒疗效提供新的策略。

The interferon (IFN) family is the most important cytokine of the first line of defense against viral infection. IFN can induce the expression of IFN-stimulated genes and exhibit antiviral function. The STAT1 protein level is critical for the activity of IFN signaling. Protein ubiquitination regulates protein levels and signaling pathways delicately, thereby playing very important roles in controlling cellular signaling transduction related to human diseases. Previously, we identified that the ubiquitin-specific protease 39(USP39) played the anti-viral function by screening of a human deubiquitinating enzymes(DUBs) siRNA library. Further experiments showed that USP39 decreased the level of STAT1 ubiquitination, thereby, stabilizing the STAT1 protein level and resulting in the enhancement of IFN signaling. In this study, we propose to further study of type I IFN signaling regulated by USP39 through gene overexpression or siRNA knockdown, the fluorescent microscopy, co-immune precipitation and other technical methods. This study will elucidate the new mechanism of USP39 for type I IFN regulation, and also provide novel basis for increasing efficiency of the anti-viral therapy in clinical.