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Cathepsin cleavage potentiates the ebola virus glycoprotein to undergo a subsequent fusion-relevant conformational change

Academic Article
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Overview

authors

  • Brecher, M.
  • Schornberg, K. L.
  • Delos, S. E.
  • Fusco, M. L.
  • Saphire, Erica Ollmann
  • White, J. M.

publication date

  • January 2012

journal

  • Journal of Virology  Journal

abstract

  • Cellular entry of Ebola virus (EBOV), a deadly hemorrhagic fever virus, is mediated by the viral glycoprotein (GP). The receptor-binding subunit of GP must be cleaved (by endosomal cathepsins) in order for entry and infection to proceed. Cleavage appears to proceed through 50-kDa and 20-kDa intermediates, ultimately generating a key 19-kDa core. How 19-kDa GP is subsequently triggered to bind membranes and induce fusion remains a mystery. Here we show that 50-kDa GP cannot be triggered to bind to liposomes in response to elevated temperature but that 20-kDa and 19-kDa GP can. Importantly, 19-kDa GP can be triggered at temperatures ∼10°C lower than 20-kDa GP, suggesting that it is the most fusion ready form. Triggering by heat (or urea) occurs only at pH 5, not pH 7.5, and involves the fusion loop, as a fusion loop mutant is defective in liposome binding. We further show that mild reduction (preferentially at low pH) triggers 19-kDa GP to bind to liposomes, with the wild-type protein being triggered to a greater extent than the fusion loop mutant. Moreover, mild reduction inactivates pseudovirion infection, suggesting that reduction can also trigger 19-kDa GP on virus particles. Our results support the hypothesis that priming of EBOV GP, specifically to the 19-kDa core, potentiates GP to undergo subsequent fusion-relevant conformational changes. Our findings also indicate that low pH and an additional endosomal factor (possibly reduction or possibly a process mimicked by reduction) act as fusion triggers.

subject areas

  • Cathepsin L
  • Cell Line
  • Ebolavirus
  • Endosomes
  • Hemorrhagic Fever, Ebola
  • Humans
  • Membrane Fusion
  • Protein Conformation
  • Protein Processing, Post-Translational
  • Viral Envelope Proteins
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Identity

PubMed Central ID

  • PMC3255896

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/jvi.05708-11

PubMed ID

  • 22031933
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Additional Document Info

start page

  • 364

end page

  • 372

volume

  • 86

issue

  • 1

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