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....

Full description

Saved in:
Bibliographic Details
Published in:The EMBO journal Vol. 31; no. 8; pp. 1947 - 1960
Main Authors: 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
Format: Journal Article
Language:English
Published: Chichester, UK John Wiley & Sons, Ltd 18.04.2012
Nature Publishing Group UK
Springer Nature B.V
Nature Publishing Group
Subjects:
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
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography: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