tetano
Editor, Senior Moderator
PLoS Pathog
. 2021 Nov 22;17(11):e1009820.
doi: 10.1371/journal.ppat.1009820. Online ahead of print.
TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction
Hataf Khan[SUP] 1 [/SUP], Helena Winstone[SUP] 1 [/SUP], Jose M Jimenez-Guardeño[SUP] 1 [/SUP], Carl Graham[SUP] 1 [/SUP], Katie J Doores[SUP] 1 [/SUP], Caroline Goujon[SUP] 2 [/SUP], David A Matthews[SUP] 3 [/SUP], Andrew D Davidson[SUP] 3 [/SUP], Suzannah J Rihn[SUP] 4 [/SUP], Massimo Palmarini[SUP] 4 [/SUP], Stuart J D Neil[SUP] 1 [/SUP], Michael H Malim[SUP] 1 [/SUP]
Affiliations
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.
. 2021 Nov 22;17(11):e1009820.
doi: 10.1371/journal.ppat.1009820. Online ahead of print.
TMPRSS2 promotes SARS-CoV-2 evasion from NCOA7-mediated restriction
Hataf Khan[SUP] 1 [/SUP], Helena Winstone[SUP] 1 [/SUP], Jose M Jimenez-Guardeño[SUP] 1 [/SUP], Carl Graham[SUP] 1 [/SUP], Katie J Doores[SUP] 1 [/SUP], Caroline Goujon[SUP] 2 [/SUP], David A Matthews[SUP] 3 [/SUP], Andrew D Davidson[SUP] 3 [/SUP], Suzannah J Rihn[SUP] 4 [/SUP], Massimo Palmarini[SUP] 4 [/SUP], Stuart J D Neil[SUP] 1 [/SUP], Michael H Malim[SUP] 1 [/SUP]
Affiliations
- PMID: 34807954
- DOI: 10.1371/journal.ppat.1009820
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.