Fusogenic structural changes in arenavirus glycoproteins are associated with viroporin activity

• Type of Material: Article
• Authors: You Zhang, Emory University; Joanne York, University of Montana; Melinda A. Brindley, University of Georgia; Jack H. Nunberg, University of Montana; Gregory Melikian, Emory University
• Language: English
• Date: 2023-07-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Zhang et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1011217
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 19
• Issue: 7
• Start Page: e1011217
• End Page: e1011217
• Grant/Funding Information: This work is supported by Division of Intramural Research, National Institute of Allergy and Infectious Diseases; NIH R01 AI053668 to GBM and NIH R01 AI139238 to MAB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: Life Sciences & Biomedicine; RECEPTOR; PH-INDUCED ACTIVATION; LASSA VIRUS ENTRY; Virology; INFLUENZA HEMAGGLUTININ; ENVELOPE GLYCOPROTEIN; CELL ENTRY; Microbiology; MEMBRANE-FUSION; JUNIN VIRUS; Parasitology; Science & Technology; PORE FORMATION; BINDING
• Research Categories: Biology, Virology; Biology, Cell; Biology, Microbiology; Biology, Parasitology

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.