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

The notable filamentous shape and stability of Ebola virus (EBOV) depend on matrix viral protein 40 (VP40). The virus enters host cells by macropinocytosis where it fuses with endosomal membrane. This study evaluated conformational changes of VP40 during virion entry and factors initiating EBOV disassembly. Characterization of EBOV using endosome mimicking conditions and in situ cryo-electron tomography showed EBOV entering host cells via the endosomal route, and the VP40 matrices were disassembled inside the endosomes. Considering the EBOV nucleocapsids were intact in all endosomes, the study postulated that uncoating of EBOV starts with disassembly of the VP40 matrix in late endosomal compartments and detachment of the matrix from viral envelope. Disassembly is followed by membrane fusion via glycoproteins and release of nucleocapsid into the cytoplasm. The Disassembly of VP40 matrix is triggered by low endosomal pH which results in weakening of VP40 interactions with negatively charged lipids. The pH-mediated VP40 disassembly was noted to be independent of other viral proteins. Using membrane modeling approach, the study reveals that disassembly of the VP40 matrix is critical for membrane fusion. The study hypothesized that the findings unveil promising target for development of virus matrix-specific weak base inhibitors for late penetrating viruses.

(LML)