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

Abstract

Ebola viruses (EBOVs) are filamentous particles, whose shape and stability are determined by the VP40 matrix. 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.

An RNA to rule them all: Critical steps in Lassa virus ribonucleoparticle assembly and recruitment

“…Unlike in influenza viruses, arenaviruses do not have proton channels in their lipid envelope that actively acidify the virion upon endocytosis. However, it has been recently shown that protons can also passively cross viral membranes leading to viral matrix reorganization in Ebola virus [56]. Besides the pH-dependent NP-Z interaction, we observed that Z starts to oligomerize between pH 5 and 5.5.…”

High curvature promotes fusion of lipid membranes: Predictions from continuum elastic theory

“…Alternatively, a theoretical analysis predicted a higher uptake rate of tubular particles over spherical ones ( 89 ), suggesting that endocytosis might be the important step affected by virus shape. Moreover, spherical and tubular virions form in different pathways, resulting in distinct lipid compositions and structures viral matrix layer, which can also affect the fusion rate ( 90 ). Therefore, further research is needed to clarify the relationship between virus shape and infectivity.…”

Viral Membrane Fusion: A Dance Between Proteins and Lipids

“…In models of pores arising directly from hemifusion stalks, fusion proteins may stabilize the stalk and mechanically drive pore opening, with associations between fusion peptides and TMDs, providing required energy (68,73,110). Changes to the underlying viral matrix may assist pore formation or expansion (111)(112)(113)(114).…”