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PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
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Xu, Dijin, Jiang, Weiqian, Wu, Lizhen, Gaudet, Ryan G., Park, Eui-Soon, Su, Maohan, Cheppali, Sudheer Kumar, Cheemarla, Nagarjuna R., Kumar, Pradeep, Uchil, Pradeep D., Grover, Jonathan R., Foxman, Ellen F., Brown, Chelsea M., Stansfeld, Phillip J., Bewersdorf, Joerg, Mothes, Walther, Karatekin, Erdem, Wilen, Craig B. and MacMicking, John D. (2023) PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature, 619 . pp. 819-827. doi:10.1038/s41586-023-06322-y ISSN 0028-0836.
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Official URL: http://dx.doi.org/10.1038/s41586-023-06322-y
Abstract
Understanding protective immunity to COVID-19 facilitates preparedness for future pandemics and combats new SARS-CoV-2 variants emerging in the human population. Neutralizing antibodies have been widely studied; however, on the basis of large-scale exome sequencing of protected versus severely ill patients with COVID-19, local cell-autonomous defence is also crucial1,2,3,4. Here we identify phospholipid scramblase 1 (PLSCR1) as a potent cell-autonomous restriction factor against live SARS-CoV-2 infection in parallel genome-wide CRISPR–Cas9 screens of human lung epithelia and hepatocytes before and after stimulation with interferon-γ (IFNγ). IFNγ-induced PLSCR1 not only restricted SARS-CoV-2 USA-WA1/2020, but was also effective against the Delta B.1.617.2 and Omicron BA.1 lineages. Its robust activity extended to other highly pathogenic coronaviruses, was functionally conserved in bats and mice, and interfered with the uptake of SARS-CoV-2 in both the endocytic and the TMPRSS2-dependent fusion routes. Whole-cell 4Pi single-molecule switching nanoscopy together with bipartite nano-reporter assays found that PLSCR1 directly targeted SARS-CoV-2-containing vesicles to prevent spike-mediated fusion and viral escape. A PLSCR1 C-terminal β-barrel domain—but not lipid scramblase activity—was essential for this fusogenic blockade. Our mechanistic studies, together with reports that COVID-associated PLSCR1 mutations are found in some susceptible people3,4, identify an anti-coronavirus protein that interferes at a late entry step before viral RNA is released into the host-cell cytosol.
Item Type: | Journal Article | ||||||||||||||||||||||||||||||
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Subjects: | Q Science > QR Microbiology R Medicine > RA Public aspects of medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | COVID-19 (Disease), COVID-19 (Disease) -- Prevention, COVID-19 (Disease) -- Treatment, Immunity | ||||||||||||||||||||||||||||||
Journal or Publication Title: | Nature | ||||||||||||||||||||||||||||||
Publisher: | Nature Publishing | ||||||||||||||||||||||||||||||
ISSN: | 0028-0836 | ||||||||||||||||||||||||||||||
Official Date: | 27 July 2023 | ||||||||||||||||||||||||||||||
Dates: |
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Volume: | 619 | ||||||||||||||||||||||||||||||
Page Range: | pp. 819-827 | ||||||||||||||||||||||||||||||
DOI: | 10.1038/s41586-023-06322-y | ||||||||||||||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||||||||
Date of first compliant deposit: | 13 July 2023 | ||||||||||||||||||||||||||||||
Date of first compliant Open Access: | 14 July 2023 | ||||||||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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