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Proteolytic Activation of SARS-CoV-2 Spike at the S1/S2 Boundary: Potential Role of Proteases beyond Furin.
ACS Infect Dis. 2021 02 12; 7(2):264-272.AI

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike (S) protein to mediate viral entry into host cells. Cleavage of the S protein at the S1/S2 and/or S2' site(s) is associated with viral entry, which can occur at either the cell plasma membrane (early pathway) or the endosomal membrane (late pathway), depending on the cell type. Previous studies show that SARS-CoV-2 has a unique insert at the S1/S2 site that can be cleaved by furin, which appears to expand viral tropism to cells with suitable protease and receptor expression. Here, we utilize viral pseudoparticles and protease inhibitors to study the impact of the S1/S2 cleavage on infectivity. Our results demonstrate that S1/S2 cleavage is essential for early pathway entry into Calu-3 cells, a model lung epithelial cell line, but not for late pathway entry into Vero E6 cells, a model cell line. The S1/S2 cleavage was found to be processed by other proteases beyond furin. Using bioinformatic tools, we also analyze the presence of a furin S1/S2 site in related CoVs and offer thoughts on the origin of the insertion of the furin-like cleavage site in SARS-CoV-2.

Links

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Authors+Show Affiliations

Tang T
Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, United States.
Jaimes JA
Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, United States.
Bidon MK
Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, United States.
Straus MR
Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, United States.
Daniel S
Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, United States.
Whittaker GR
Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, United States.

MeSH

AnimalsCOVID-19Cell LineChlorocebus aethiopsFurinHEK293 CellsHumansModels, MolecularPeptide HydrolasesProteolysisSARS-CoV-2Spike Glycoprotein, CoronavirusVero CellsVirus Internalization

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33432808

Citation

Tang, Tiffany, et al. "Proteolytic Activation of SARS-CoV-2 Spike at the S1/S2 Boundary: Potential Role of Proteases Beyond Furin." ACS Infectious Diseases, vol. 7, no. 2, 2021, pp. 264-272.
Tang T, Jaimes JA, Bidon MK, et al. Proteolytic Activation of SARS-CoV-2 Spike at the S1/S2 Boundary: Potential Role of Proteases beyond Furin. ACS Infect Dis. 2021;7(2):264-272.
Tang, T., Jaimes, J. A., Bidon, M. K., Straus, M. R., Daniel, S., & Whittaker, G. R. (2021). Proteolytic Activation of SARS-CoV-2 Spike at the S1/S2 Boundary: Potential Role of Proteases beyond Furin. ACS Infectious Diseases, 7(2), 264-272. https://doi.org/10.1021/acsinfecdis.0c00701
Tang T, et al. Proteolytic Activation of SARS-CoV-2 Spike at the S1/S2 Boundary: Potential Role of Proteases Beyond Furin. ACS Infect Dis. 2021 02 12;7(2):264-272. PubMed PMID: 33432808.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proteolytic Activation of SARS-CoV-2 Spike at the S1/S2 Boundary: Potential Role of Proteases beyond Furin. AU - Tang,Tiffany, AU - Jaimes,Javier A, AU - Bidon,Miya K, AU - Straus,Marco R, AU - Daniel,Susan, AU - Whittaker,Gary R, Y1 - 2021/01/12/ PY - 2021/1/13/pubmed PY - 2021/2/26/medline PY - 2021/1/12/entrez KW - S1/S2 site KW - SARS-CoV-2 KW - cleavage KW - furin KW - viral entry SP - 264 EP - 272 JF - ACS infectious diseases JO - ACS Infect Dis VL - 7 IS - 2 N2 - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike (S) protein to mediate viral entry into host cells. Cleavage of the S protein at the S1/S2 and/or S2' site(s) is associated with viral entry, which can occur at either the cell plasma membrane (early pathway) or the endosomal membrane (late pathway), depending on the cell type. Previous studies show that SARS-CoV-2 has a unique insert at the S1/S2 site that can be cleaved by furin, which appears to expand viral tropism to cells with suitable protease and receptor expression. Here, we utilize viral pseudoparticles and protease inhibitors to study the impact of the S1/S2 cleavage on infectivity. Our results demonstrate that S1/S2 cleavage is essential for early pathway entry into Calu-3 cells, a model lung epithelial cell line, but not for late pathway entry into Vero E6 cells, a model cell line. The S1/S2 cleavage was found to be processed by other proteases beyond furin. Using bioinformatic tools, we also analyze the presence of a furin S1/S2 site in related CoVs and offer thoughts on the origin of the insertion of the furin-like cleavage site in SARS-CoV-2. SN - 2373-8227 UR - https://www.unboundmedicine.com/medline/citation/33432808/Proteolytic_Activation_of_SARS_CoV_2_Spike_at_the_S1/S2_Boundary:_Potential_Role_of_Proteases_beyond_Furin_ DB - PRIME DP - Unbound Medicine ER -