PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection

Dijin Xu, Weiqian Jiang, Lizhen Wu, Ryan G. Gaudet, Eui-Soon Park, Maohan Su, Sudheer Kumar Cheppali, Nagarjuna R. Cheemarla, Pradeep Kumar, Pradeep D. Uchil, Jonathan R. Grover, Ellen F. Foxman, Chelsea M. Brown, Phillip J. Stansfeld, Joerg Bewersdorf, Walther Mothes, Erdem Karatekin, Craig B. Wilen and John D. MacMicking ()
Additional contact information
Dijin Xu: Howard Hughes Medical Institute
Weiqian Jiang: Howard Hughes Medical Institute
Lizhen Wu: Yale University School of Medicine
Ryan G. Gaudet: Howard Hughes Medical Institute
Eui-Soon Park: Howard Hughes Medical Institute
Maohan Su: Yale University School of Medicine
Sudheer Kumar Cheppali: Yale Nanobiology Institute
Nagarjuna R. Cheemarla: Yale University School of Medicine
Pradeep Kumar: Howard Hughes Medical Institute
Pradeep D. Uchil: Yale University School of Medicine
Jonathan R. Grover: Yale University School of Medicine
Ellen F. Foxman: Yale University School of Medicine
Chelsea M. Brown: University of Warwick
Phillip J. Stansfeld: University of Warwick
Joerg Bewersdorf: Yale University School of Medicine
Walther Mothes: Yale University School of Medicine
Erdem Karatekin: Yale Nanobiology Institute
Craig B. Wilen: Yale University School of Medicine
John D. MacMicking: Howard Hughes Medical Institute

Nature, 2023, vol. 619, issue 7971, 819-827

Abstract: 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 crucial1–4. 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.

Date: 2023
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DOI: 10.1038/s41586-023-06322-y

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