宿主蛋白PGRN调控I型干扰素的功能和机制研究

In recent years, studies demonstrated that progranulin (PGRN) plays an essential role in inflammatory response, neurodegenerative disorder and pathogenic microorganism infection. In previous research of our group, we first detected that IFN-I expression significantly enhanced to resist influenza A virus infection in the PGRN deletion mice. And we also demonstrated PGRN negatively regulates the IFN-I signaling pathway. However, the specific detail of this negative regulatory mechanism remains unclear and PGRN effects IFN-I production in innate immune response has not been reported yet. In this study, we intend to screen key signaling molecules interacting with PGRN via Liquid Chromatography-mass Spectrometry(LC-MS), probe into the mechanism of PGRN and IFN-I interaction, and further reveal the mechanism of PGRN negative regulation in innate immunity. The research will help to fully understand the regulation network of innate immunity, and provide theoretical support for antiviral targets selection.

近年来，颗粒素蛋白前体(progranulin，PGRN)已经被证实在炎症应答、神经退行性疾病以及病原体感染过程中扮演重要角色。本课题组前期研究首次发现PGRN基因缺失型的小鼠能显著增强IFN-I的产生，从而抵抗A型流感病毒感染；并且证实了PGRN对IFN-I信号通路具有负调控作用，但其机制仍不清楚。本研究拟利用双荧光素报告系统和蛋白质液相色谱-质谱技术筛选与PGRN相互作用的关键信号分子，探究PGRN对关键信号分子的表达和翻译后修饰的影响，进一步揭示PGRN负调控IFN-I抗病毒天然免疫信号通路的作用机制。研究成果有助于发展和完善机体抗病毒天然免疫的调控网络理论，为抗病毒靶点的选择提供新思路。

颗粒素蛋白前体(progranulin, PGRN)已经被证实在炎症应答、神经退行性疾病及病原体感染过程中具有重要作用，前期研究已发现PGRN基因缺失小鼠能显著增强I型干扰素(IFN-I)的产生，从而抵抗A型流感病毒的感染。但是PGRN对IFN-I信号通路调控作用机制以及流感病毒逃逸IFN-I介导的抗病毒应答机制仍有待进一步阐明。本课题利用双荧光素报告系统和蛋白质液相色谱-质谱技术筛选与PGRN相互作用的关键信号分子，探究PGRN对关键信号分子的表达和翻译后修饰的影响。利用PGRN敲低实验和PGRN缺陷小鼠模型，证实流感病毒诱导产生的PGRN可以通过抑制NF-κB和IRF3信号通路的激活负调控I型干扰素的产生，以及PGRN通过其CDE结构域直接与NF-κB essential modulator (NEMO)相互作用，PGRN通过招募去泛素化酶A20催化NEMO蛋白k63连接去泛素化。本课题解析了一种宿主蛋白介导的流感病毒逃逸I型干扰素抗病毒应答的机制，该机制被流感病毒利用，具有抗病毒应用价值。这些发现也为PGRN在先天免疫中的功能和作用提供了的新见解。