TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction

Khan, H. et al. (2021) TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction. PLoS Pathogens, 17(11), e1009820. (doi: 10.1371/journal.ppat.1009820) (PMID:34807954) (PMCID:PMC8648102)

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Interferons play a critical role in regulating host immune responses to SARS-CoV-2, but the interferon (IFN)-stimulated gene (ISG) effectors that inhibit SARS-CoV-2 are not well characterized. The IFN-inducible short isoform of human nuclear receptor coactivator 7 (NCOA7) inhibits endocytic virus entry, interacts with the vacuolar ATPase, and promotes endo-lysosomal vesicle acidification and lysosomal protease activity. Here, we used ectopic expression and gene knockout to demonstrate that NCOA7 inhibits infection by SARS-CoV-2 as well as by lentivirus particles pseudotyped with SARS-CoV-2 Spike in lung epithelial cells. Infection with the highly pathogenic, SARS-CoV-1 and MERS-CoV, or seasonal, HCoV-229E and HCoV-NL63, coronavirus Spike-pseudotyped viruses was also inhibited by NCOA7. Importantly, either overexpression of TMPRSS2, which promotes plasma membrane fusion versus endosomal fusion of SARS-CoV-2, or removal of Spike’s polybasic furin cleavage site rendered SARS-CoV-2 less sensitive to NCOA7 restriction. Collectively, our data indicate that furin cleavage sensitizes SARS-CoV-2 Spike to the antiviral consequences of endosomal acidification by NCOA7, and suggest that the acquisition of furin cleavage may have favoured the co-option of cell surface TMPRSS proteases as a strategy to evade the suppressive effects of IFN-induced endo-lysosomal dysregulation on virus infection.

Item Type:Articles
Additional Information:This work was funded by King’s Together Rapid COVID-19 Call awards to MHM, SJDN and KJD; the Wellcome Trust (106223/Z/14/Z to MHM); a Huo Family Foundation Award to MHM, SJDN, and KJD; and NIAID Award U54 AI150472 to MHM. We acknowledge the Genotype-to-Phenotype UK National Virology Consortium funded by MRC/UKRI (MR/W005611/1) and Public Health England for providing viral isolates. HW and CG were supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). This work was supported by the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (MHM).
Keywords:SARS CoV 2, luciferase, SARS coronavirus, respiratory infections, coronaviruses, membrane fusion, COVID 19, proteases.
Glasgow Author(s) Enlighten ID:Rihn, Dr Suzannah and Palmarini, Professor Massimo
Creator Roles:
Rihn, S. J.Resources
Palmarini, M.Resources
Authors: Khan, H., Winstone, H., Jimenez-Guardeño, J. M., Graham, C., Doores, K. J., Goujon, C., Matthews, D. A., Davidson, A. D., Rihn, S. J., Palmarini, M., Neil, S. J. D., and Malim, M. H.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN (Online):1553-7374
Published Online:22 November 2021
Copyright Holders:Copyright © 2021 Khan et al.
First Published:First published in PLoS Pathogens 17(11): e1009820
Publisher Policy:Reproduced under a Creative Commons License

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