ArticleJournal of virology2010
A forward genetic strategy reveals destabilizing mutations in the Ebolavirus glycoprotein that alter its protease dependence during cell entry.
Article in Journal of virology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers.
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Who cites it
121 citing papers in PubMed, 156 citations in OpenAlex.
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- How endosomal PIKfyve inhibition prevents viral membrane fusion and entry.bioRxiv : the preprint server for biology · 2025Article
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- Characterization of Ravn virus viral shedding dynamics in experimentally infected Egyptian rousette bats (Journal of virology · 2025Article
- A replicating recombinant vesicular stomatitis virus model for dairy cattle H5N1 influenza virus glycoprotein evolution.bioRxiv : the preprint server for biology · 2025Article
- Decoding the blueprint of receptor binding by filoviruses through large-scale binding assays and machine learning.Cell host & microbe · 2025Article
- Multiple cell types support productive infection and dynamic translocation of infectious Ebola virus to the surface of human skin.Science advances · 2025Article
- SuFEx-enabled high-throughput medicinal chemistry for developing potent tamoxifen analogs as Ebola virus entry inhibitors.Frontiers in immunology · 2025Article
- Distinct pathways for evolution of enhanced receptor binding and cell entry in SARS-like bat coronaviruses.PLoS pathogens · 2024Article
- Establishment of replication-competent vesicular stomatitis virus recapitulating SADS-CoV entry.Journal of virology · 2024Article
- Design and characterization of protective pan-ebolavirus and pan-filovirus bispecific antibodies.PLoS pathogens · 2024Article
- A viral vaccine design harnessing prior BCG immunization confers protection against Ebola virus.Frontiers in immunology · 2024Article
- Modification of N-Linked Glycan Sites in Viral Glycoproteins.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody.Science translational medicine · 2023Article
- Replicating-Competent VSV-Vectored Pseudotyped Viruses.Advances in experimental medicine and biology · 2023Article
- Filoviruses: Innate Immunity, Inflammatory Cell Death, and Cytokines.Pathogens (Basel, Switzerland) · 2022Review
61 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Ebolavirus (EBOV) entry into cells requires proteolytic disassembly of the viral glycoprotein, GP. This proteolytic processing, unusually extensive for an enveloped virus entry protein, is mediated by cysteine cathepsins, a family of endosomal/lysosomal proteases. Previous work has shown that cleavage of GP by cathepsin B (CatB) is specifically required to generate a critical entry intermediate. The functions of this intermediate are not well understood. We used a forward genetic strategy to investigate this CatB-dependent step. Specifically, we generated a replication-competent recombinant vesicular stomatitis virus bearing EBOV GP as its sole entry glycoprotein and used it to select viral mutants resistant to a CatB inhibitor. We obtained mutations at six amino acid positions in GP that independently confer complete resistance. All of the mutations reside at or near the GP1-GP2 intersubunit interface in the membrane-proximal base of the prefusion GP trimer. This region forms a part of the "clamp" that holds the fusion subunit GP2 in its metastable prefusion conformation. Biochemical studies suggest that most of the mutations confer CatB independence not by altering specific cleavage sites in GP but rather by inducing conformational rearrangements in the prefusion GP trimer that dramatically enhance its susceptibility to proteolysis. The remaining mutants did not show the preceding behavior, indicating the existence of multiple mechanisms for acquiring CatB independence during entry. Altogether, our findings suggest that CatB cleavage is required to facilitate the triggering of viral membrane fusion by destabilizing the prefusion conformation of EBOV GP.
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