Unraveling a three-step spatiotemporal mechanism of triggering of receptor-induced Nipah virus fusion and cell entry

PLoS Pathog. 2013;9(11):e1003770. doi: 10.1371/journal.ppat.1003770. Epub 2013 Nov 21.

Abstract

Membrane fusion is essential for entry of the biomedically-important paramyxoviruses into their host cells (viral-cell fusion), and for syncytia formation (cell-cell fusion), often induced by paramyxoviral infections [e.g. those of the deadly Nipah virus (NiV)]. For most paramyxoviruses, membrane fusion requires two viral glycoproteins. Upon receptor binding, the attachment glycoprotein (HN/H/G) triggers the fusion glycoprotein (F) to undergo conformational changes that merge viral and/or cell membranes. However, a significant knowledge gap remains on how HN/H/G couples cell receptor binding to F-triggering. Via interdisciplinary approaches we report the first comprehensive mechanism of NiV membrane fusion triggering, involving three spatiotemporally sequential cell receptor-induced conformational steps in NiV-G: two in the head and one in the stalk. Interestingly, a headless NiV-G mutant was able to trigger NiV-F, and the two head conformational steps were required for the exposure of the stalk domain. Moreover, the headless NiV-G prematurely triggered NiV-F on virions, indicating that the NiV-G head prevents premature triggering of NiV-F on virions by concealing a F-triggering stalk domain until the correct time and place: receptor-binding. Based on these and recent paramyxovirus findings, we present a comprehensive and fundamentally conserved mechanistic model of paramyxovirus membrane fusion triggering and cell entry.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Henipavirus Infections / genetics
  • Henipavirus Infections / metabolism
  • Membrane Fusion Proteins / genetics
  • Membrane Fusion Proteins / metabolism*
  • Nipah Virus / physiology*
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Internalization*

Substances

  • Glycoproteins
  • Membrane Fusion Proteins
  • Receptors, Virus
  • Viral Proteins