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A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells
Open accessAbstract
The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.
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“The S protein is cleaved into S1 and S2 subunits during viral infection by the Furin enzyme and transmembrane serine protease 2 (TMPRSS2).231,232”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [231]
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Metadata
- Authors
- Hoffmann, M., Kleine-Weber, H., & Pöhlmann, S.
- Affiliations
- German Primate Center (DE)
- Corresponding author
- Hoffmann, Markus
- Pöhlmann, Stefan
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 78
- Issue
- 4
- Pages
- 779-784.e5
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC7194065
- OpenAlex
- W3017302293
- Cited by
- 1,852
- References
- 52
- Citations by year
- 2026: 60 · 2025: 116 · 2024: 182 · 2023: 228 · 2022: 396 · 2021: 542 · 2020: 327
- FWCI
- 48.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesministerium für Bildung und Forschung (01KI1723D)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, spike protein, S1/S2 cleavage site, furin, proteolytic cleavage, cell-cell fusion, viral entry, human lung cells, viral variants, virulence, therapeutic target
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Animals, Cell Line, Chlorocebus aethiops, Humans, Lung, Pneumonia, Viral, Serine Endopeptidases, Vero Cells, Coronavirus Infections, Furin, Virus Attachment, Pandemics, Spike Glycoprotein, Coronavirus
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