Fusogenic structural changes in arenavirus glycoproteins are associated with viroporin activity

You Zhang, Joanne York, Melinda A. Brindley, Jack H. Nunberg, Gregory B. Melikyan

Research output: Contribution to journalArticlepeer-review

Abstract

Many enveloped viruses enter host cells by fusing with acidic endosomes. The fusion activity of multiple viral envelope glycoproteins does not generally affect viral membrane permeability. However, fusion induced by the Lassa virus (LASV) glycoprotein complex (GPc) is always preceded by an increase in viral membrane permeability and the ensuing acidification of the virion interior. Here, systematic investigation of this LASV fusion phenotype using single pseudovirus tracking in live cells reveals that the change in membrane barrier function is associated with the fusogenic conformational reorganization of GPc. We show that a small-molecule fusion inhibitor or mutations that impair viral fusion by interfering with GPc refolding into the post-fusion structure prevent the increase in membrane permeability. We find that the increase in virion membrane permeability occurs early during endosomal maturation and is facilitated by virus-cell contact. This increase is observed using diverse arenavirus glycoproteins, whether presented on lentivirus-based pseudoviruses or arenavirus-like particles, and in multiple different cell types. Collectively, these results suggest that conformational changes in GPc triggered by low pH and cell factor binding are responsible for virion membrane permeabilization and acidification of the virion core prior to fusion. We propose that this viroporin-like activity may augment viral fusion and/or post-fusion steps of infection, including ribonucleoprotein release into the cytoplasm.

Original languageEnglish
Article numbere1011217
Pages (from-to)e1011217
JournalPLoS Pathogens
Volume19
Issue number7
DOIs
StatePublished - Jul 2023

Keywords

  • Arenavirus/genetics
  • Viroporin Proteins/metabolism
  • Glycoproteins/metabolism
  • Viral Envelope Proteins/metabolism
  • Lassa virus
  • Virus Internalization

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