دورية أكاديمية
Spike Protein Cleavage-Activation in the Context of the SARS-CoV-2 P681R Mutation: an Analysis from Its First Appearance in Lineage A.23.1 Identified in Uganda.
| العنوان: | Spike Protein Cleavage-Activation in the Context of the SARS-CoV-2 P681R Mutation: an Analysis from Its First Appearance in Lineage A.23.1 Identified in Uganda. |
|---|---|
| المؤلفون: | Lubinski B; Graduate Program in Biological & Biomedical Sciences, Cornell Universitygrid.5386.8, Ithaca, New York, USA.; Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell Universitygrid.5386.8, Ithaca, New York, USA., Frazier LE; Graduate Program in Biological & Biomedical Sciences, Cornell Universitygrid.5386.8, Ithaca, New York, USA., Phan MVT; MRC/UVRI and London School of Hygiene and Tropical Medicine - Uganda Research Unit, Entebbe, Uganda., Bugembe DL; MRC/UVRI and London School of Hygiene and Tropical Medicine - Uganda Research Unit, Entebbe, Uganda., Cunningham JL; Graduate Program in Biological & Biomedical Sciences, Cornell Universitygrid.5386.8, Ithaca, New York, USA., Tang T; Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell Universitygrid.5386.8, Ithaca, New York, USA., Daniel S; Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell Universitygrid.5386.8, Ithaca, New York, USA., Cotten M; MRC/UVRI and London School of Hygiene and Tropical Medicine - Uganda Research Unit, Entebbe, Uganda.; MRC Centre of Virus Research, University of Glasgow, Glasgow, United Kingdom., Jaimes JA; Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell Universitygrid.5386.8, Ithaca, New York, USA., Whittaker GR; Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell Universitygrid.5386.8, Ithaca, New York, USA.; Department of Public and Ecosystem Health, College of Veterinary Medicine, Cornell Universitygrid.5386.8, Ithaca, New York, USA. |
| المصدر: | Microbiology spectrum [Microbiol Spectr] 2022 Aug 31; Vol. 10 (4), pp. e0151422. Date of Electronic Publication: 2022 Jun 29. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: ASM Press Country of Publication: United States NLM ID: 101634614 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2165-0497 (Electronic) Linking ISSN: 21650497 NLM ISO Abbreviation: Microbiol Spectr Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : ASM Press, 2013- |
| مواضيع طبية MeSH: | COVID-19*/virology , SARS-CoV-2*/genetics , Spike Glycoprotein, Coronavirus*/genetics , Spike Glycoprotein, Coronavirus*/metabolism, Furin/genetics ; Furin/metabolism ; Humans ; Mutation ; Uganda |
| مستخلص: | Based on its predicted ability to affect transmissibility and pathogenesis, surveillance studies have highlighted the role of a specific mutation (P681R) in the S1/S2 furin cleavage site of the SARS-CoV-2 spike protein. Here we analyzed A.23.1, first identified in Uganda, as a P681R-containing virus several months prior to the emergence of B.1.617.2 (Delta variant). We performed assays using peptides mimicking the S1/S2 from A.23.1 and B.1.617 and observed significantly increased cleavability with furin compared to both an original B lineage (Wuhan-Hu1) and B.1.1.7 (Alpha variant). We also performed cell-cell fusion and functional infectivity assays using pseudotyped particles and observed an increase in activity for A.23.1 compared to an original B lineage spike. However, these changes in activity were not reproduced in the B lineage spike bearing only the P681R substitution. Our findings suggest that while A.23.1 has increased furin-mediated cleavage linked to the P681R substitution, this substitution needs to occur on the background of other spike protein changes to enable its functional consequences. IMPORTANCE During the course of the SARS-CoV-2 pandemic, viral variants have emerged that often contain notable mutations in the spike gene. Mutations that encode changes in the spike S1/S2 (furin) activation site have been considered especially impactful. The S1/S2 change from proline to arginine at position 681 (P681R) first emerged in the A.23.1 variant in Uganda, and subsequently occurred in the more widely transmitted Delta variant. We show that the A.23.1 spike is more readily activated by the host cell protease furin, but that this is not reproduced in an original SARS-CoV-2 spike containing the P681R mutation. Changes to the S1/S2 (furin) activation site play a role in SARS-CoV-2 infection and spread, but successful viruses combine these mutations with other less well identified changes, occurring as part of natural selection. |
| التعليقات: | Update of: bioRxiv. 2022 Mar 28;:. (PMID: 34230931) |
| References: | Nat Microbiol. 2021 Aug;6(8):1094-1101. (PMID: 34163035) EMBO J. 2021 Dec 15;40(24):e108944. (PMID: 34601723) J Mol Biol. 2020 May 1;432(10):3309-3325. (PMID: 32320687) Sci Transl Med. 2021 May 26;13(595):. (PMID: 33941621) Nat Commun. 2021 Sep 29;12(1):5705. (PMID: 34588460) Nature. 2021 Apr;592(7852):122-127. (PMID: 33636719) J Virol. 1985 Dec;56(3):904-11. (PMID: 2999443) J Vis Exp. 2019 Mar 1;(145):. (PMID: 30882796) Nat Microbiol. 2021 Jul;6(7):899-909. (PMID: 33907312) Cell Rep. 2022 May 17;39(7):110829. (PMID: 35550680) Lancet Microbe. 2021 Oct;2(10):e488-e489. (PMID: 34396356) Cell. 2020 Apr 16;181(2):271-280.e8. (PMID: 32142651) iScience. 2022 Jan 21;25(1):103589. (PMID: 34909610) Nat Microbiol. 2020 Nov;5(11):1403-1407. (PMID: 32669681) Sci Rep. 2012;2:261. (PMID: 22355773) Curr Opin Virol. 2021 Apr;47:113-120. (PMID: 33744490) Emerg Infect Dis. 2021 Dec;27(12):3133-3136. (PMID: 34708685) Lancet Microbe. 2021 Feb;2(2):e53-e54. (PMID: 33521708) Nat Rev Microbiol. 2021 Jul;19(7):409-424. (PMID: 34075212) Protein Eng Des Sel. 2004 Jan;17(1):107-12. (PMID: 14985543) Cell. 2021 Mar 4;184(5):1127-1132. (PMID: 33581746) Nature. 2021 Mar;591(7849):293-299. (PMID: 33494095) J Vis Exp. 2019 Jan 9;(143):. (PMID: 30688313) Nat Rev Drug Discov. 2012 May;11(5):367-83. (PMID: 22679642) Virus Evol. 2022 Aug 26;8(2):veac080. (PMID: 36533153) J Virol. 2010 Sep;84(17):8683-90. (PMID: 20554779) iScience. 2020 Jun 26;23(6):101212. (PMID: 32512386) Nature. 2022 Feb;602(7896):300-306. (PMID: 34823256) Science. 2021 Oct 22;374(6566):423-431. (PMID: 34672751) Cell. 2020 Oct 29;183(3):739-751.e8. (PMID: 32991842) J Gen Virol. 2021 Apr;102(4):. (PMID: 33855951) |
| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; MC_PC_19026 United Kingdom MRC_ Medical Research Council; MC_PC_20010 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: A.23.1; P681R mutation; SARS-CoV-2; Uganda; spike |
| المشرفين على المادة: | 0 (Spike Glycoprotein, Coronavirus) 0 (spike protein, SARS-CoV-2) EC 3.4.21.75 (Furin) |
| SCR Organism: | SARS-CoV-2 variants |
| تواريخ الأحداث: | Date Created: 20220629 Date Completed: 20220908 Latest Revision: 20240205 |
| رمز التحديث: | 20240205 |
| مُعرف محوري في PubMed: | PMC9430374 |
| DOI: | 10.1128/spectrum.01514-22 |
| PMID: | 35766497 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder كن أول من يترك تعليقا!