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

Emily Happy Miller, Gregor Obernosterer, Matthijs Raaben, Andrew S. Herbert, Maika S. Deffieu, Anuja Krishnan, Esther Ndungo, Rohini G. Sandesara, Jan E. Carette, Ana I. Kuehne, Gordon Ruthel, Suzanne R. Pfeffer, John M. Dye, Sean P. Whelan, Thijn R. Brummelkamp, Kartik Chandran

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187 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1947-1960
Number of pages14
JournalEMBO Journal
Volume31
Issue number8
DOIs
StatePublished - Apr 18 2012

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Keywords

  • Ebola virus
  • Marburg virus
  • Niemann-Pick C1
  • viral entry
  • viral receptor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Miller, E. H., Obernosterer, G., Raaben, M., Herbert, A. S., Deffieu, M. S., Krishnan, A., Ndungo, E., Sandesara, R. G., Carette, J. E., Kuehne, A. I., Ruthel, G., Pfeffer, S. R., Dye, J. M., Whelan, S. P., Brummelkamp, T. R., & Chandran, K. (2012). Ebola virus entry requires the host-programmed recognition of an intracellular receptor. EMBO Journal, 31(8), 1947-1960. https://doi.org/10.1038/emboj.2012.53