Ebola virus entry requires the host-programmed recognition of an intracellular receptor
Ebola virus entry requires the host-programmed recognition of an intracellular receptor
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DOI：
10.1038/emboj.2012.53
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发表时间：
2012-04-18
期刊：
影响因子：
11.4
通讯作者：
Chandran, Kartik
中科院分区：
文献类型：
--
作者：
Miller, Emily Happy;Obernosterer, Gregor;Chandran, Kartik
埃博拉病毒和马尔堡丝状病毒会导致致命的出血热暴发。尽管做出了相当大的努力，但尚未鉴定出丝状病毒进入的必需细胞受体。我们以前表明，尼曼-皮克C1（NPC 1），溶酶体胆固醇转运蛋白，是丝状病毒进入所必需的。在这里，我们证明了NPC 1是一个关键的丝状病毒受体。人NPC 1实现了病毒受体的基本特性：当在非允许的爬行动物细胞中表达时，它赋予对丝状病毒感染的易感性。NPC 1的第二个管腔结构域直接特异性结合病毒糖蛋白GP，含有该结构域的合成单程膜蛋白具有病毒受体活性。纯化的NPC 1仅与进入细胞期间在细胞内产生的切割形式的GP结合，并且仅含有切割的GP的病毒可以利用重新靶向细胞表面的受体。我们的研究结果支持一个模型，其中GP裂解的内体半胱氨酸蛋白酶揭露NPC 1的结合位点，和GP-NPC 1参与内溶酶体促进进入近端病毒逃逸到宿主细胞质的后期步骤。NPC 1是第一个已知的在细胞内而不是在质膜上识别其配体的病毒受体。The EMBO Journal（2012）31，1947-1960. doi：10.1038/djj.2012.53;在线发布2012年3月6日主题分类：膜和运输;微生物学和病原体
Ebola and Marburg filoviruses cause deadly outbreaks of haemorrhagic fever. Despite considerable efforts, no essential cellular receptors for filovirus entry have been identified. We showed previously that Niemann-Pick C1 (NPC1), a lysosomal cholesterol transporter, is required for filovirus entry. Here, we demonstrate that NPC1 is a critical filovirus receptor. Human NPC1 fulfills a cardinal property of viral receptors: it confers susceptibility to filovirus infection when expressed in non-permissive reptilian cells. The second luminal domain of NPC1 binds directly and specifically to the viral glycoprotein, GP, and a synthetic single-pass membrane protein containing this domain has viral receptor activity. Purified NPC1 binds only to a cleaved form of GP that is generated within cells during entry, and only viruses containing cleaved GP can utilize a receptor retargeted to the cell surface. Our findings support a model in which GP cleavage by endosomal cysteine proteases unmasks the binding site for NPC1, and GP-NPC1 engagement within lysosomes promotes a late step in entry proximal to viral escape into the host cytoplasm. NPC1 is the first known viral receptor that recognizes its ligand within an intracellular compartment and not at the plasma membrane. The EMBO Journal (2012) 31, 1947-1960. doi:10.1038/emboj.2012.53; Published online 6 March 2012 Subject Categories: membranes & transport; microbiology & pathogens