USP21 参与调控I型干扰素信号通路机制和功能的研究

Diseases caused by virus infection are great threats to human health. When the virus infected hosts, increased expression of type I interferons and induced antiviral gene expression make the hosts resist viral infections. Therefore, the study of antiviral signaling pathway is crucial for human health. STING is a adapter protein which is essential for type I interferon expression and cellular antiviral response.STING’s ubiquitination plays an important role in virus-induced type I interferon generation. It is unknown to the deubiquitination enzymes involved in this process. The project intends to use deubiquitination enzymes reported gene screening assay, screening out the deubiquitinase USP21 play an important role in STING-dependent type I interferons production. We will use fluorescence quantitative PCR , western immunoblotting, elisa, gene deletion mouse model to study USP21 function and mechanism. The research about STING, USP21 and cellular anti-virus effect relationship will clarify the molecular mechanisms of USP21 regulating type I interferon signaling pathway , to provide new ideas for antiviral drug research, and to offer theoretical basis for human antiviral treatment .

病毒感染宿主所引发的疾病是人类健康的巨大威胁之一。病毒感染宿主后，I型干扰素的表达增多进而诱导大量抗病毒基因表达，从而使得宿主抵抗病毒感染。因此对于抗病毒的信号通路调控的研究是至关重要的。STING是I型干扰素表达及细胞抗病毒反应至关重要的接头蛋白，而STING泛素化修饰在病毒诱导I型干扰素产生过程中的起着重要的作用。在这个过程中，可能有未知去泛素化酶参与到这个过程，本项目拟利用去泛素化酶报告基因筛选的实验方法，筛选出去泛素化酶USP21参与STING激活的I型干扰素的过程。我们将通过荧光定量PCR,免疫印迹，Elisa，基因缺失小鼠模型的方法研究USP21对于STING的抗病毒作用。研究STING、USP21与细胞抗病毒效应三者的关系，阐明USP21在调控I型干扰素信号通路的分子机机制，为针对抗病毒新药研究提供新思路，为人类抗病毒药物治疗提供理论依椐。

STING作为DNA病毒信号通路关键性的接头蛋白，有着极其重要的功能，尽管其泛素化修饰已经被报道对其功能极为重要，但是泛素化修饰如何平衡的还是未知。我们的发现研究显示 去泛素化酶USP21能够去K27/63泛素化的STING并且调控其抗DNA病毒的功能，HSV-1感染的过程中能激活P38进而磷酸化USP21丝氨酸538位，增强其与STING的相互作用，而抑制p38的活性能保护小鼠不被HSV-1感染致死。我们的研究揭示了在DNA病毒感染过程中p38-USP21-STING轴能抑制过度免疫反应。