Ebola virus entry requires the host-programmed recognition of an intracellular receptor

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....

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Vydáno v:	The EMBO journal Ročník 31; číslo 8; s. 1947 - 1960
Hlavní autoři:	Miller, Emily Happy, Obernosterer, Gregor, Raaben, Matthijs, Herbert, Andrew S, Deffieu, Maika S, Krishnan, Anuja, Ndungo, Esther, Sandesara, Rohini G, Carette, Jan E, Kuehne, Ana I, Ruthel, Gordon, Pfeffer, Suzanne R, Dye, John M, Whelan, Sean P, Brummelkamp, Thijn R, Chandran, Kartik
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Chichester, UK John Wiley & Sons, Ltd 18.04.2012 Nature Publishing Group UK Springer Nature B.V Nature Publishing Group
Témata:	Animals Binding sites Carrier Proteins - metabolism Cell Line Cholesterol Ebola virus Ebolavirus - physiology EMBO20 EMBO23 Filovirus Glycoproteins Humans Marburg virus Membrane Glycoproteins - metabolism Membranes Microbiology Models, Biological Models, Molecular Molecular biology Niemann-Pick C1 Outbreaks Protein Binding Receptors, Virus - metabolism Viperidae viral entry Viral Envelope Proteins - chemistry Viral Envelope Proteins - metabolism viral receptor Virus Internalization Ebola virus viral entry Marburg virus Niemann‐Pick C1 viral receptor
ISSN:	0261-4189, 1460-2075, 1460-2075
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Shrnutí:	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. Niemann‐Pick C1 (NPC1), a lysosomal cholesterol transporter, is known to be required for Ebola virus entry. Here, NPC1 is shown to be sufficient for Ebola infection by directly binding the viral glycoprotein, GP, after its NPC1‐binding site is unmasked by endosomal protease cleavage.
Bibliografie:	ark:/67375/WNG-0SLS527X-8 ArticleID:EMBJ201253 Supplementary InformationSource file for Figure 1Source file for Figure 2Source file for Figure 3Source file for Figure 4Source file for Figure 5Source file for Figure 7Source file for Figure S4Source file for Figure S5Source file for Figure S6Source file for Figure S7Source file for Figure S9Source file for Figure S10Review Process File istex:B1D753319548C5BBE5C0F4AD39C2A59A5D5E988E ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Present address: Institute of Molecular Medicine, New Delhi, India These authors contributed equally to this work
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.1038/emboj.2012.53