The DOI matches its Crossref record; 49 of the 52 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A novel coronavirus from patients with pneumonia in China, 2019
Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2001017 · Cited by 28,244
A pneumonia outbreak associated with a new coronavirus of probable bat origin
Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L., Zhang, W., Si, H.-R., Zhu, Y., Li, B., Huang, C.-L., et al. (2020) · Nature · doi:10.1038/s41586-020-2012-7 · Cited by 21,969
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286
Self-citationCryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C.-L., Abiona, O., Graham, B. S., & McLellan, J. S. (2020) · Science · doi:10.1126/science.abb2507 · Cited by 8,897
Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Walls, A. C., Park, Y.-J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020) · doi:10.1101/2020.02.19.956581 · Cited by 8,586
A novel coronavirus outbreak of global health concern
Wang, C., Horby, P. W., Hayden, F. G., & Gao, G. F. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30185-9 · Cited by 7,700
The EMBL-EBI search and sequence analysis tools APIs in 2019
Madeira, F., Park, Y. M., Lee, J., Buso, N., Gur, T., Madhusoodanan, N., Basutkar, P., Tivey, A. R. N., Potter, S. C., Finn, R. D., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz268 · Cited by 4,167
Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins
Lam, T. T., Jia, N., Zhang, Y.-W., Shum, M. H.-H., Jiang, J.-F., Zhu, H., Tong, Y., Shi, Y., Ni, X.-B., Liao, Y., et al. (2020) · Nature · doi:10.1038/s41586-020-2169-0 · Cited by 1,877
Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor
Ge, X.-Y., Li, J.-L., Yang, X.-L., Chmura, A. A., Zhu, G., Epstein, J. H., Mazet, J. K., Hu, B., Zhang, W., Peng, C., et al. (2013) · Nature · doi:10.1038/nature12711 · Cited by 1,778
YASARA View—molecular graphics for all devices—from smartphones to workstations
Krieger, E., & Vriend, G. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu426 · Cited by 1,573
Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak
Zhang, T., Wu, Q., & Zhang, Z. (2020) · Current Biology · doi:10.1016/j.cub.2020.03.022 · Cited by 1,397
Glowacka, I., Bertram, S., Müller, M. A., Allen, P. W., Soilleux, E. J., Pfefferle, S., Steffen, I., Tsegaye, T. S., He, Y., Gnirß, K., et al. (2011) · Journal of Virology · doi:10.1128/jvi.02232-10 · Cited by 1,130
Self-citationInhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry
Simmons, G., Gosalia, D. N., Rennekamp, A. J., Reeves, J. D., Diamond, S. L., & Bates, P. F. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505577102 · Cited by 1,052
Matsuyama, S., Nagata, N., Shirato, K., Kawase, M., Takeda, M., & Taguchi, F. (2010) · Journal of Virology · doi:10.1128/jvi.01542-10 · Cited by 778
Yuan, Y., Cao, D., Zhang, Y., Ma, J., Qi, J., Wang, Q., Lu, G., Wu, Y., Yan, J., Shi, Y., et al. (2017) · Nature Communications · doi:10.1038/ncomms15092 · Cited by 756
Shulla, A., Heald-Sargent, T. A., Subramanya, G., Zhao, J., Perlman, S. M., & Gallagher, T. (2010) · Journal of Virology · doi:10.1128/jvi.02062-10 · Cited by 705
Millet, J. K., & Whittaker, G. R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1407087111 · Cited by 673
Iwata‐Yoshikawa, N., Okamura, T., Shimizu, Y., Hasegawa, H., Takeda, M., & Nagata, N. (2019) · Journal of Virology · doi:10.1128/jvi.01815-18 · Cited by 607
Zhou, H., Chen, X., Hu, T., Li, J., Song, H., Liu, Y., Wang, P., Liu, D., Yang, J., Holmes, E. C., et al. (2020) · Current Biology · doi:10.1016/j.cub.2020.05.023 · Cited by 589
Protease inhibitors targeting coronavirus and filovirus entry
Zhou, Y., Vedantham, P., Lü, K., Agudelo, J., Carrion, R., Nunneley, J. W., Barnard, D. L., Pöhlmann, S., McKerrow, J. H., Renslo, A. R., et al. (2015) · Antiviral Research · doi:10.1016/j.antiviral.2015.01.011 · Cited by 588
Self-citationCoronavirus Spike Protein and Tropism Changes
Hulswit, R. J. G., de Haan, C. A. M., & Bosch, B. (2016) · Advances in virus research · doi:10.1016/bs.aivir.2016.08.004 · Cited by 469
Shirato, K., Kawase, M., & Matsuyama, S. (2013) · Journal of Virology · doi:10.1128/jvi.01890-13 · Cited by 448
Evolutionary history, potential intermediate animal host, and cross‐species analyses of SARS‐CoV‐2
Li, X., Zai, J., Zhao, Q., Nie, Q. H., Li, Y., Foley, B. T., & Chaillon, A. (2020) · Journal of Medical Virology · doi:10.1002/jmv.25731 · Cited by 428
Gierer, S., Bertram, S., Kaup, F. ‐., Wrensch, F., Heurich, A., Krämer-Kühl, A., Welsch, K., Winkler, M., Meyer, B., Drosten, C., et al. (2013) · Journal of Virology · doi:10.1128/jvi.00128-13 · Cited by 346
Self-citationBertram, S., Dijkman, R., Habjan, M., Heurich, A., Gierer, S., Glowacka, I., Welsch, K., Winkler, M., Schneider, H., Hofmann-Winkler, H., et al. (2013) · Journal of Virology · doi:10.1128/jvi.03372-12 · Cited by 341
Self-citationProteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism
Park, J.-E., Li, K., Barlan, A., Fehr, A. R., Perlman, S. M., McCray, P. B., & Gallagher, T. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1608147113 · Cited by 306
Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin
Roebroek, A., Umans, L., Pauli, I. G. L., Robertson, E. J., LEUVEN, F. V., de Ven, W. J. M. V., & Constam, D. B. (1998) · Development · doi:10.1242/dev.125.24.4863 · Cited by 304
Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells
Millet, J. K., & Whittaker, G. R. (2017) · Virology · doi:10.1016/j.virol.2017.12.015 · Cited by 293
Yang, Y., Du, L., Liu, C., Wang, L., Ma, C., Tang, J., Baric, R. S., Jiang, S., & Li, F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405889111 · Cited by 279
Berger Rentsch, M., & Zimmer, G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025858 · Cited by 269
Inhibitors of SARS-CoV‑2 Entry: Current and Future Opportunities
Xiu, S., Dick, A., Ju, H., Mirzaie, S., Abdi, F., Cocklin, S., Zhan, P., & Liu, X. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00502 · Cited by 227
Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection
Menachery, V. D., Dinnon, K. H., Yount, B. L., McAnarney, E. T., Gralinski, L. E., Hale, A., Graham, R. L., Scobey, T., Anthony, S. J., Wang, L., et al. (2020) · Journal of Virology · doi:10.1128/jvi.01774-19 · Cited by 205
Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract
Ortiz, M. E., Thurman, A. L., Pezzulo, A. A., Leidinger, M., Klesney‐Tait, J., Karp, P. H., Tan, P., Wohlford-Lenane, C., McCray, P. B., & Meyerholz, D. K. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102976 · Cited by 199
Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein
Kleine‐Weber, H., Elzayat, M. T., Hoffmann, M., & Pöhlmann, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-34859-w · Cited by 164
Self-citationKleine‐Weber, H., Elzayat, M. T., Wang, L., Graham, B. S., Müller, M. A., Drosten, C., Pöhlmann, S., & Hoffmann, M. (2018) · Journal of Virology · doi:10.1128/jvi.01381-18 · Cited by 143
Self-citationClinical Isolates of Human Coronavirus 229E Bypass the Endosome for Cell Entry
Shirato, K., Kanou, K., Kawase, M., & Matsuyama, S. (2016) · Journal of Virology · doi:10.1128/jvi.01387-16 · Cited by 139
Hoffmann, M., Müller, M. A., Drexler, J. F., Glende, J., Erdt, M., Gützkow, T., Losemann, C., Binger, T., Deng, H., Schwegmann‐Weßels, C., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072942 · Cited by 114
Self-citationPriming Time: How Cellular Proteases Arm Coronavirus Spike Proteins
Hoffmann, M., Hofmann-Winkler, H., & Pöhlmann, S. (2018) · Springer eBooks · doi:10.1007/978-3-319-75474-1_4 · Cited by 104
Self-citationSARS-CoV-2 COVID-19 susceptibility and lung inflammatory storm by smoking and vaping
Kaur, G., Lungarella, G., & Rahman, I. (2020) · Journal of Inflammation · doi:10.1186/s12950-020-00250-8 · Cited by 102
Sarač, M. S., Cameron, A., & Lindberg, I. (2002) · Infection and Immunity · doi:10.1128/iai.70.12.7136-7139.2002 · Cited by 85
Herrera, N. G., Morano, N. C., Celikgil, A., Georgiev, G. I., Malonis, R. J., Lee, J. H., Tong, K., Vergnolle, O., Massimi, A. B., Yen, L. Y., et al. (2020) · ACS Omega · doi:10.1021/acsomega.0c03512 · Cited by 84
Luczo, J. M., Stambas, J., Durr, P. A., Michalski, W. P., & Bingham, J. (2015) · Reviews in Medical Virology · doi:10.1002/rmv.1846 · Cited by 83
Protection against Anthrax Toxemia by Hexa- d -Arginine In Vitro and In Vivo
Sarač, M. S., Peinado, J. R., Leppla, S. H., & Lindberg, I. (2003) · Infection and Immunity · doi:10.1128/iai.72.1.602-605.2004 · Cited by 81
Activation of Viruses by Host Proteases
Friebertshäuser, E., Garten, W., & Klenk, H. (2019) · Cambridge International Law Journal · doi:10.1007/978-3-319-75474-1 · Cited by 49
Brinkmann, C., Hoffmann, M., Lübke, A., Nehlmeier, I., Krämer-Kühl, A., Winkler, M., & Pöhlmann, S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0189073 · Cited by 47
Self-citationZhou, H., Chen, X., Hu, T., Li, J., Song, H., Liu, Y., Wang, P., Liu, D., Yang, J., Holmes, E. C., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.02.974139 · Cited by 40
Gierer, S., Müller, M. A., Heurich, A., Ritz, D., Springstein, B. L., Karsten, C. B., Schendzielorz, A. B., Gnirß, K., Drosten, C., & Pöhlmann, S. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiu407 · Cited by 39
Self-citationSchwegmann‐Weßels, C., Glende, J., Ren, X., Qu, X., Deng, H., Enjuanes, L., & Herrler, G. (2009) · Journal of General Virology · doi:10.1099/vir.0.009704-0 · Cited by 38
Can SARS-CoV-2 infect the eye? An overview of the receptor status in ocular tissue
Schnichels, S., Rohrbach, J. M., Bayyoud, T., Thaler, S., Ziemssen, F., & Hurst, J. (2020) · Der Ophthalmologe · doi:10.1007/s00347-020-01281-5 · Cited by 28
Flagged first, then by citations
3 of the 52 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
SARS-CoV-2 variants, spike mutations and immune escape
Harvey, W. T., Carabelli, A. M., Jackson, B., Gupta, R. K., Thomson, E. C., Harrison, E. M., Ludden, C., Reeve, R., Rambaut, A., COVID-19 Genomics UK (COG-UK) Consortium, et al. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00573-0 · Cited by 3,528
Coronavirus biology and replication: implications for SARS-CoV-2
V’kovski, P., Kratzel, A., Steiner, S., Stalder, H., & Thiel, V. (2020) · Nature Reviews Microbiology · doi:10.1038/s41579-020-00468-6 · Cited by 3,371
Mechanisms of SARS-CoV-2 entry into cells
Jackson, C. B., Farzan, M., Chen, B., & Choe, H. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00418-x · Cited by 3,022
Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England
Davies, N. G., Abbott, S., Barnard, R. C., Jarvis, C. I., Kucharski, A. J., Munday, J. D., Pearson, C. A. B., Russell, T. W., Tully, D. C., Washburne, A. D., et al. (2021) · Science · doi:10.1126/science.abg3055 · Cited by 2,581
“Peak ICU requirement 9,880 (9,240 - 10,500) 5,830 (5,450 - 6,220) 4,720 (4,450 - 4,960) 4,340 (4,110 - 4,550)”
BackgroundInfluentialNeuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity
Cantuti-Castelvetri, L., Ojha, R., Pedro, L. D., Djannatian, M., Franz, J., Kuivanen, S., van der Meer, F., Kallio, K., Kaya, T., Anastasina, M., et al. (2020) · Science · doi:10.1126/science.abd2985 · Cited by 1,925
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
