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

• DOI: 10.1371/journal.ppat.1009820
• Publication Date: 2021-11-22T18:35:05Z
• Authors: Hataf Khan; Helena Winstone; Jose M. Jimenez-G...; Carl Graham; Katie J. Doores; Caroline Goujon; David A. Matthews; Andrew D. Davidson; Suzannah J. Rihn; Massimo Palmarini; Stuart J. D. Neil; Michael H. Malim
• Keywords: 0301 basic medicine; QH301-705.5; Nuclear Receptor Coactivators; Gene Expression; Endosomes; Cell Line; 03 medical and health sciences; Humans; Protein Isoforms; Viral Pseudotyping; Biology (General); Immune Evasion; Furin; SARS-CoV-2; Serine Endopeptidases; COVID-19; RC581-607; Virus Internalization; 3. Good health; Proteolysis; Spike Glycoprotein, Coronavirus; Interferons; Immunologic diseases. Allergy; Lysosomes; Research Article

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.