泛素化修饰介导的干扰素诱导跨膜蛋白3双向调控包膜病毒感染侵入机制的研究

干扰素诱导跨膜蛋白3（IFITM3）是机体细胞重要抗病毒分子，抑制多种包膜病毒对宿主细胞的感染侵入。既往研究发现IFITM3是病毒感染单纯限制性因子，且泛素化修饰可促进其蛋白降解，对其负性调控。申请人首次发现IFITM3抑制流感病毒侵入的同时，还显著促进人冠状病毒OC43感染(PNAS，2014)，提示IFITM3对包膜病毒侵入起双向调控作用。并进一步发现：IFITM3对病毒侵入的双向调控，均依赖IFITM3的泛素化修饰 (JVI，2018)，并发现两组不同泛素化位点的赖氨酸残基分别与IFITM3抑制或促进病毒侵入相关。因此，申请人提出全新假说 “不同位点赖氨酸残基泛素化修饰，介导IFITM3双向调控病毒侵入”。 本研究将研究IFITM3如何通过泛素化修饰，调控其亚细胞定位及蛋白互作，最终影响包膜病毒侵入，揭示IFITM3对包膜病毒侵入双向调控深入机制，为抗病毒药物的研发提供理论依据。

Interferon-induced transmembrane protein3 (IFITM3) provides the first line of antiviral defense, by inhibiting the infectious entry of a wide variety of enveloped viruses. Previous studies indicated that IFITM3 only play an inhibitory effect on viral entry, and is downregulated by ubiquitination-mediated degradation. Our recent work published in PNAS demonstrated that IFITM3 promotes the infection of HCoV-OC43 but restricts the entry of influenza virus, indicating IFITM3 play a bidirectional function of modulating the entry of enveloped viruses. Our continued study found that ubiquitination modification is required for IFITM3 modulating virlal entry, and further identified two distinct groups of ubiquitinated Lysine residues are essential for the restriction versus enhancing activity of IFITM3 on viral entry. We thus proposed a new model "ubiquitination mediates IFITM3 bidirectionally modulating viral entry of enveloped viruses". In this study, we are going to investigate how ubiquitination occurring at different lysine residues control IFITM3 trafficking, subcellular location, and oligomerization, which consequently determines the restriction versus enhancing activity of IFITM3 on viral entry. Our work would reveal novel mechanism of how IFITM3 ubiquitination control viral entry and advance our knowledge in development of novel antiviral therapeutics.