免疫缺陷病毒Vpx蛋白识别宿主CRL4（DCAF1）E3泛素连接酶的作用机制研究

Human Immunodeficiency Virus (HIV) as the major cause of the most severe infectious disease- acquired immune deficiency syndrome(AIDS), has always been the research hotspots in the field of virology worldwide. Viral protein X (Vpx) encoded by HIV-2 and related simian immunodeficiency virus (SIV), is able to facilitate viral infectivity in monocyte-derived macrophages (MDMs) through hijack cellular CRL4(DCAF1) E3 ligase to induce host restriction factor SAMHD1 ubiquitination and degradation. Vpx-CRL4(DCAF1) E3 ligase serves as potential antiviral targets and has become the cutting edge in the research field of virus-host interaction. However, the understanding of the precisely regulative mechanism of viral protein Vpx usurp host E3 ligase is poor. Previously, the applicant has clarified the molecular properties of viral protein Vpx, the functional regulation by post-translational modification neddylation, and the interaction with substrate SAMHD1. Based on these results, the project will further investigate the function of Vpx protein from diverse research perspectives，to identify novel weak points of the activities of Vpx-CRL4(DCAF1) E3 ligase; the interaction with cellular suppressor of CRL4(DCAF1) E3 liagse, Merlin; and the reverse regulation of the target protein SAMHD1 on Vpx function. The project will extend our understanding of the strategies of viral protein Vpx utilization of host E3 ligase which would be helpful for designing a novel inhibitor targeting a novel attractive antiviral pharmacologic intervention.

免疫缺陷病毒HIV作为艾滋病的主要诱因，一直是国际病毒学界的研究热点。由HIV-2和同源病毒SIV编码的Vpx蛋白通过识别CRL4(DCAF1) E3连接酶诱导巨噬细胞内天然抗病毒因子SAMHD1泛素化降解，被认为是潜在的重大抗病毒作用靶点。但是，病毒蛋白Vpx占用宿主泛素化连接酶的分子策略和作用机制仍有待深入研究。本项目将基于申请人在Vpx蛋白的分子特性、类泛素化Neddylation调控、底物识别等方面已获得的研究基础，以全新的研究视角，系统性的分析Vpx-CRL4(DCAF1) E3连接酶的新脆弱点、Vpx蛋白与CRL4(DCAF1)复合体限制因子Merlin的作用关系以及底物SAMHD1对上游Vpx-CRL4(DCAF1) E3连接酶的反向调控机制。本项目的开展将进一步拓展领域对病毒蛋白参与的泛素化复合体活性调节的认识，对合理设计具有针对性的新型抑制剂作用靶点具有重要的指导意义。

本项目基于申请人在Vpx蛋白的分子特性、类泛素化Neddylation调控、底物识别等方面已获得的研究基础，以全新的研究视角，系统性的分析了Vpx-CRL4(DCAF1) E3连接酶的新脆弱点-Vpx锌离子结合功能结构域、Vpx蛋白与CRL4(DCAF1)复合体限制因子Merlin的作用关系以及底物SAMHD1对上游Vpx-CRL4(DCAF1) E3连接酶的反向调控机制。本项目的开展对进一步拓展领域对病毒蛋白参与的泛素化复合体活性调节的认识，对合理设计具有针对性的新型抑制剂作用靶点具有重要的指导意义。