Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
EMBO J. 2012 Apr 18;31(8):1947-60. doi: 10.1038/emboj.2012.53. Epub 2012 Mar 6.
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.
埃博拉病毒和马尔堡病毒属的丝状病毒可引起致命性出血热疫情。尽管已付出巨大努力，但仍未鉴定出丝状病毒进入的必需细胞受体。我们之前曾表明，溶酶体胆固醇转运蛋白 Niemann-Pick C1（NPC1）是丝状病毒进入所必需的。在这里，我们证明 NPC1 是一种关键的丝状病毒受体。人 NPC1 满足病毒受体的主要特性：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。NPC1 的第二个腔内结构域可直接且特异性地与病毒糖蛋白（GP）结合，并且包含该结构域的合成单次跨膜蛋白具有病毒受体活性。纯化的 NPC1 仅与在进入过程中在细胞内产生的切割形式的 GP 结合，并且只有包含切割 GP 的病毒才能利用靶向细胞表面的受体进行再靶向。我们的发现支持以下模型：内体半胱氨酸蛋白酶对 GP 的切割使 NPC1 的结合位点暴露，并且 GP-NPC1 在溶酶体中的结合促进了进入过程中接近病毒逃逸到宿主细胞质的晚期步骤。NPC1 是第一个已知在细胞内隔室而不是在质膜内识别其配体的病毒受体。
