人类冠状病毒逃避/抑制宿主抗病毒天然免疫机制还不清楚。申请者在国家基金项目系列研究中发现，PLP蛋白酶是冠状病毒编码的一种新型IFN拮抗蛋白。课题组最新研究发现，PLP蛋白酶能特异性诱导自噬(Autophagy)，是一种病毒来源的新型自噬诱导蛋白。目前对PLP诱导自噬及其在天然免疫调节中的作用还不清楚。本项目以前期研究发现为基础，围绕"人类冠状病毒调节宿主抗病毒天然免疫机制"这一科学问题，提出"PLP蛋白酶通过激活细胞自噬信号通路调节抗病毒天然免疫"科学假设。针对该设想，课题拟综合应用分子生物学和分子免疫学技术，研究人类冠状病毒PLP蛋白酶对细胞自噬信号通路调节及其分子机制；细胞自噬信号通路在PLP蛋白酶调节抗病毒天然免疫中作用及其分子机制。课题对研究人类新发冠状病毒PLP蛋白酶新功能，揭示冠状病毒抑制/逃避抗病毒天然免疫及其机制，发现新型抗病毒免疫干预措施具有重要理论意义。

Human coronaviruses (CoV) have developed strategies to evade and subvert the host antiviral innate immune response. However, the molecular mechanisms that human coronaviruses evade or block the complex signaling pathway of host innate immunity still remain unclear.Our previous research found that Papain-like protease (PLP) containing within coronavirus non-structural protein 3 (Nsp3), one of the processed products of coronavirus replicase polyprotein, functions as both viral protease and deubiquitinase (DUB) and acts as IFN antagonist. Our unpublished data further confirmed that SARS-CoV PLP induces activation of autophagy, an essential process for physiological homeostasis. Autophagy-associated signaling pathway has been implicated in the modulation of host antiviral innate immunity. However, the functional interaction between regulation of innate immunity and induction of autophagy of human coronavirus PLP remains poorly understood. In this project, we hypothesis a new mechanism that human coronavirus Papain-like protease (PLP) modulates the antiviral innate immunity through targeting autophagy and activating autophagy-associated signaling pathway. We propose: 1) to determine if coronavirus papain-like protease (PLP) modulates the autophagy and if PLP domains from other coronaviruses exploit similar or distinct mechanisms for modulation of autophagy. 2) to determine how PLP modulates autuphagy through targeting autuphagy-related signaling pathway. 3) to determine if modulation of autophagy pathway is associated with the negative regulation of innate immunity of coronavirus PLP. and 4) to determine the regulation mechanisms of antiviral innate immunity through targeting autophagy signaling protein complex by human coronavirus PLP. The project will provide new information on the role of coronavirus PLP in blocking or inactivating the innate immune system and identify potential targets for antiviral immunological interventions for human coronavirus infection.