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The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13
Biochemical and structural analyses suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) efficiently infects humans, and the presence of four residues (PRRA) at the S1/S2 site within the spike (S) protein may lead to unexpected tissue or host tropism. Here, we report that SARS-C...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Microbiology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139715/ https://www.ncbi.nlm.nih.gov/pubmed/33685917 http://dx.doi.org/10.1128/JVI.01751-20 |
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author | Liu, Shufeng Selvaraj, Prabhuanand Lien, Christopher Z. Nunez, Ivette A. Wu, Wells W. Chou, Chao-Kai Wang, Tony T. |
author_facet | Liu, Shufeng Selvaraj, Prabhuanand Lien, Christopher Z. Nunez, Ivette A. Wu, Wells W. Chou, Chao-Kai Wang, Tony T. |
author_sort | Liu, Shufeng |
collection | PubMed |
description | Biochemical and structural analyses suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) efficiently infects humans, and the presence of four residues (PRRA) at the S1/S2 site within the spike (S) protein may lead to unexpected tissue or host tropism. Here, we report that SARS-CoV-2 efficiently utilized angiotensin-converting enzyme 2 (ACE2) of 9 species to infect 293T cells. Similarly, pseudoviruses bearing S protein derived from either bat RaTG13 or pangolin GX, two closely related animal coronaviruses, utilized ACE2 of a diverse range of animal species to gain entry. The removal of PRRA from SARS-CoV-2 S protein displayed distinct effects on pseudoviral entry into different cell types. Unexpectedly, the insertion of PRRA into the RaTG13 S protein selectively abrogated the usage of horseshoe bat and pangolin ACE2 but enhanced the usage of mouse ACE2 by the relevant pseudovirus to enter cells. Together, our findings identified a previously unrecognized effect of the PRRA insert on SARS-CoV-2 and RaTG13 S proteins. IMPORTANCE The four-residue insert (PRRA) at the boundary between the S1 and S2 subunits of SARS-CoV-2 has been widely recognized since day 1 for its role in SARS-CoV-2 S protein processing and activation. As this PRRA insert is unique to SARS-CoV-2 among group b betacoronaviruses, it is thought to affect the tissue and species tropism of SARS-CoV-2. We compared the usages of 10 ACE2 orthologs and found that the presence of PRRA not only affects the cellular tropism of SARS-CoV-2 but also modulates the usage of ACE2 orthologs by the closely related bat RaTG13 S protein. The binding of pseudovirions carrying RaTG13 S with a PRRA insert to mouse ACE2 was nearly 2-fold higher than that of pseudovirions carrying RaTG13 S. |
format | Online Article Text |
id | pubmed-8139715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-81397152021-06-14 The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13 Liu, Shufeng Selvaraj, Prabhuanand Lien, Christopher Z. Nunez, Ivette A. Wu, Wells W. Chou, Chao-Kai Wang, Tony T. J Virol Virus-Cell Interactions Biochemical and structural analyses suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) efficiently infects humans, and the presence of four residues (PRRA) at the S1/S2 site within the spike (S) protein may lead to unexpected tissue or host tropism. Here, we report that SARS-CoV-2 efficiently utilized angiotensin-converting enzyme 2 (ACE2) of 9 species to infect 293T cells. Similarly, pseudoviruses bearing S protein derived from either bat RaTG13 or pangolin GX, two closely related animal coronaviruses, utilized ACE2 of a diverse range of animal species to gain entry. The removal of PRRA from SARS-CoV-2 S protein displayed distinct effects on pseudoviral entry into different cell types. Unexpectedly, the insertion of PRRA into the RaTG13 S protein selectively abrogated the usage of horseshoe bat and pangolin ACE2 but enhanced the usage of mouse ACE2 by the relevant pseudovirus to enter cells. Together, our findings identified a previously unrecognized effect of the PRRA insert on SARS-CoV-2 and RaTG13 S proteins. IMPORTANCE The four-residue insert (PRRA) at the boundary between the S1 and S2 subunits of SARS-CoV-2 has been widely recognized since day 1 for its role in SARS-CoV-2 S protein processing and activation. As this PRRA insert is unique to SARS-CoV-2 among group b betacoronaviruses, it is thought to affect the tissue and species tropism of SARS-CoV-2. We compared the usages of 10 ACE2 orthologs and found that the presence of PRRA not only affects the cellular tropism of SARS-CoV-2 but also modulates the usage of ACE2 orthologs by the closely related bat RaTG13 S protein. The binding of pseudovirions carrying RaTG13 S with a PRRA insert to mouse ACE2 was nearly 2-fold higher than that of pseudovirions carrying RaTG13 S. American Society for Microbiology 2021-05-10 /pmc/articles/PMC8139715/ /pubmed/33685917 http://dx.doi.org/10.1128/JVI.01751-20 Text en This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. https://doi.org/10.1128/ASMCopyrightv2This article is made available via the PMC Open Access Subset for unrestricted noncommercial re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Virus-Cell Interactions Liu, Shufeng Selvaraj, Prabhuanand Lien, Christopher Z. Nunez, Ivette A. Wu, Wells W. Chou, Chao-Kai Wang, Tony T. The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13 |
title | The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13 |
title_full | The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13 |
title_fullStr | The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13 |
title_full_unstemmed | The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13 |
title_short | The PRRA Insert at the S1/S2 Site Modulates Cellular Tropism of SARS-CoV-2 and ACE2 Usage by the Closely Related Bat RaTG13 |
title_sort | prra insert at the s1/s2 site modulates cellular tropism of sars-cov-2 and ace2 usage by the closely related bat ratg13 |
topic | Virus-Cell Interactions |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139715/ https://www.ncbi.nlm.nih.gov/pubmed/33685917 http://dx.doi.org/10.1128/JVI.01751-20 |
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