@article{Khan_H-2021_63787,
title = {TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction},
author = {Khan, H. and Winstone, H. and Jimenez-Guardeño, J. and Graham, C. and Doores, K. and Goujon, C. and Matthews, D. and Davidson, A. and Rihn, S. and Palmarini, M. and Neil, S. and Malim, M.},
month = {nov},
year = {2021},
abstract = {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.},
volume = {17},
issue = {11},
journal = {PLoS Pathogens},
publisher = {Public Library of Science},
url = {http://dx.doi.org/10.1371/journal.ppat.1009820},
}
