TY - JOUR
AU - Khan, Hataf
AU - Winstone, Helena
AU - Jimenez-Guardeño, Jose M.
AU - Graham, Carl
AU - Doores, Katie J.
AU - Goujon, Caroline
AU - Matthews, David A.
AU - Davidson, Andrew D.
AU - Rihn, Suzannah J.
AU - Palmarini, Massimo
AU - Neil, Stuart J.D.
AU - Malim, Michael H.
PY - 2021
DA - November
TI - TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction
JO - PLoS Pathogens
VL - 17
IS - 11
DO - http://dx.doi.org/10.1371/journal.ppat.1009820
AB - 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.
PB - Public Library of Science
UR - http://eprints.gla.ac.uk/259802/
KW - Coronavirus (COVID-19)
ER