The Ebola virus VP40 matrix layer undergoes endosomal disassembly essential for membrane fusion

Sophie L. Winter, Gonen Golani, Fabio Lolicato, Melina Vallbracht, Keerthihan Thiyagarajah, Samy Sid Ahmed, Christian Lüchtenborg, Oliver T. Fackler, Britta Brügger, Thomas Hoenen, Walter Nickel, Ulrich S. Schwarz, Petr Chlanda

Research output: Contribution to journalArticlepeer-review

Abstract

Ebola viruses (EBOVs) assemble into filamentous virions, whose shape and stability are determined by the matrix viral protein 40 (VP40). Virus entry into host cells occurs via membrane fusion in late endosomes; however, the mechanism of how the remarkably long virions undergo uncoating, including virion disassembly and nucleocapsid release into the cytosol, remains unknown. Here, we investigate the structural architecture of EBOVs entering host cells and discover that the VP40 matrix disassembles prior to membrane fusion. We reveal that VP40 disassembly is caused by the weakening of VP40–lipid interactions driven by low endosomal pH that equilibrates passively across the viral envelope without a dedicated ion channel. We further show that viral membrane fusion depends on VP40 matrix integrity, and its disassembly reduces the energy barrier for fusion stalk formation. Thus, pH-driven structural remodeling of the VP40 matrix acts as a molecular switch coupling viral matrix uncoating to membrane fusion during EBOV entry.

Original languageEnglish
Article numbere113578
JournalEMBO Journal
Volume42
Issue number11
DOIs
StatePublished - 1 Jun 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

  • Ebola virus
  • in situ cryo-ET
  • membrane fusion
  • membrane modeling and molecular dynamics simulations
  • virus entry and uncoating

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • Molecular Biology
  • General Neuroscience

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