干扰素诱导蛋白MxB抑制Vimentin介导病毒胞内转运的机制研究

MxB is a novel antiviral host factor which inhibits a broad-spectrum virus. It makes sense to IFN-mediated innate immunity by further research on the antiviral activities of MxB. The mechanism of MxB inhibiting HIV, HSV and HCV has not been fully clarified. According to recent research, MxB possibly blocks the nuclear uptake of viral replication complexes or prevents the uncoating process of HIV. Our research indicates MxB can disrupt NS5A association with CypA and prevent NS5A localization to the ER. Result of Mass Spectrum shows that MxB interacts with Vimentin belonging to the type III of intermediate filament proteins. The normal processes of nuclear import, uncoating or transport of viral protein rely on the stable cytoskeleton and motor proteins. Taken together, we propose that MxB inhibits virus replication by interrupting Vimentin-dependent transportation of viral particles or proteins. We will prove the hypothesis from the following three aspects: 1) The mechanism of the interaction between MxB and Vimentin, and the effect of which on antiviral activity of MxB.2) The function of Vimentin in transport of viral particle or protein. 3) The mechanism of MxB inhibiting Vimentin-dependent transport of virus. Fully understanding of the mechanism of MxB inhibiting virus replication helps the discovery of new anti-viral drug targets and the development of disease control and prevention.

新近发现干扰素诱导蛋白MxB具有广谱的抗病毒能力，可以有效抑制HIV-1等逆转录病毒、HSV和HCV的复制，但其作用机制作尚不清楚，成为本领域的研究热点。研究表明MxB可以干扰HIV-1、HSV病毒颗粒的入核过程，影响HCV NS5A蛋白的ER区定位，提示其可能干扰病毒及病毒蛋白在胞内转运。已知病毒和病毒蛋白胞内转运过程依赖于细胞骨架及动力蛋白，而我们的前期研究发现MxB与细胞骨架蛋白Vimentin相互作用，且与其抗病毒活性密切相关。据此，我们提出了“MxB干扰骨架蛋白Vimentin介导的病毒颗粒以及蛋白转运过程这一广谱抗病毒新机制”。为了验证这一假说，我们拟研究1）Vimentin与MxB互作机制及其在MxB抗病毒活性中的作用；2）Vimentin在病毒及病毒蛋白胞内转运中的功能；3）MxB抑制Vimentin胞内转运功能的机制。本课题旨在阐明MxB广谱抗病毒活性的分子机制。

干扰素通过自身信号通路激活一系列的抗病毒宿主蛋白表达，在先天性免疫抗病毒过程中发挥重要作用。粘液病毒抗性蛋白B（MxB）作为一个干扰素激活蛋白已被报导对多种病毒具有抑制活性，但其广谱抗病毒机制有待进一步探索。本项目通过质谱分析发现MxB参与干扰素对宿主蛋白亚细胞定位的调控过程，进一步研究发现MxB与中间微丝蛋白Vimentin存在直接相互作用，并且能募集蛋白激酶Akt针对Vimentin氨基酸序列中38位的丝氨酸进行磷酸化。该磷酸化能显著诱导Vimentin进行结构重排，进而影响病毒蛋白或核酸在细胞骨架蛋白上的转运，最终导致病毒感染水平的显著降低。该发现提示我们MxB通过调控Vimentin结构实现抑制Vimentin复制依赖病毒的感染，这也为MxB广谱抗病毒机制研究提供非常有意义的思路。