The Ebola Virus Matrix Protein Penetrates into the Plasma Membrane A KEY STEP IN VIRAL PROTEIN 40 (VP40) OLIGOMERIZATION AND VIRAL EGRESS
The Ebola Virus Matrix Protein Penetrates into the Plasma Membrane A KEY STEP IN VIRAL PROTEIN 40 (VP40) OLIGOMERIZATION AND VIRAL EGRESS
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DOI：
10.1074/jbc.m112.443960
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发表时间：
2013-02-22
影响因子：
4.8
通讯作者：
Stahelin, Robert V.
中科院分区：
文献类型：
--
作者：
Adu-Gyamfi, Emmanuel;Soni, Smita P.;Stahelin, Robert V.
埃博拉病毒是一种在人类和非人类灵长类动物中致命的病毒，没有食品和药物管理局批准的疫苗或治疗药物。来自丝状病毒科的病毒引起出血热，其迅速进展，并且在某些情况下具有接近90%的死亡率。埃博拉病毒基因组编码7个基因，其中表达最丰富的是病毒蛋白40（VP 40），这是调节病毒组装和外出的主要埃博拉病毒基质蛋白。已确定VP 40在质膜的内小叶上组装;然而，VP 40与质膜结合的机制细节尚未完全了解。在这项研究中，我们使用了一系列的生物物理实验和细胞分析沿着与突变的VP 40研究膜渗透的作用，在VP 40的组装和出口。在这里，我们证明，VP 40是能够通过在其C-末端结构域中的疏水残基丰富的接口，特异性地渗透到质膜。由Leu（213）、Ile（293）、Leu（295）和瓦尔（298）组成的该疏水区的突变表明，膜渗透对于质膜定位、VP 40寡聚化和病毒颗粒排出至关重要。总之，VP 40膜渗透是基质蛋白质膜定位的重要步骤，其中在不存在与膜的关键疏水相互作用的情况下寡聚化和出芽是有缺陷的。
Ebola, a fatal virus in humans and non-human primates, has no Food and Drug Administration-approved vaccines or therapeutics. The virus from the Filoviridae family causes hemorrhagic fever, which rapidly progresses and in some cases has a fatality rate near 90%. The Ebola genome encodes seven genes, the most abundantly expressed of which is viral protein 40 (VP40), the major Ebola matrix protein that regulates assembly and egress of the virus. It is well established that VP40 assembles on the inner leaflet of the plasma membrane; however, the mechanistic details of plasma membrane association by VP40 are not well understood. In this study, we used an array of biophysical experiments and cellular assays along with mutagenesis of VP40 to investigate the role of membrane penetration in VP40 assembly and egress. Here we demonstrate that VP40 is able to penetrate specifically into the plasma membrane through an interface enriched in hydrophobic residues in its C-terminal domain. Mutagenesis of this hydrophobic region consisting of Leu(213), Ile(293), Leu(295), and Val(298) demonstrated that membrane penetration is critical to plasma membrane localization, VP40 oligomerization, and viral particle egress. Taken together, VP40 membrane penetration is an important step in the plasma membrane localization of the matrix protein where oligomerization and budding are defective in the absence of key hydrophobic interactions with the membrane.