Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

Alice Mac Kain, Ghizlane Maarifi, Sophie-Marie Aicher, Nathalie Arhel, Artem Baidaliuk, Sandie Munier, Flora Donati, Thomas Vallet, Quang Dinh Tran, Alexandra Hardy, Maxime Chazal, Françoise Porrot, Molly OhAinle, Jared Carlson-Stevermer, Jennifer Oki, Kevin Holden, Gert Zimmer, Etienne Simon-Lorière, Timothée Bruel, Olivier Schwartz, Sylvie van der Werf, Nolwenn Jouvenet (), Sébastien Nisole (), Marco Vignuzzi () and Ferdinand Roesch ()
Additional contact information
Alice Mac Kain: Université de Paris Cité
Ghizlane Maarifi: , Université de Montpellier, CNRS
Sophie-Marie Aicher: Université de Paris Cité
Nathalie Arhel: , Université de Montpellier, CNRS
Artem Baidaliuk: Institut Pasteur, G5 Evolutionary genomics of RNA viruses
Sandie Munier: Université de Paris Cité
Flora Donati: Université de Paris Cité
Thomas Vallet: Université de Paris Cité
Quang Dinh Tran: Université de Paris Cité
Alexandra Hardy: Université de Paris Cité
Maxime Chazal: Université de Paris Cité
Françoise Porrot: Université de Paris Cité
Molly OhAinle: Fred Hutchinson Cancer Research Center
Jared Carlson-Stevermer: Synthego Corporation
Jennifer Oki: Synthego Corporation
Kevin Holden: Synthego Corporation
Gert Zimmer: University of Bern
Etienne Simon-Lorière: Institut Pasteur, G5 Evolutionary genomics of RNA viruses
Timothée Bruel: Université de Paris Cité
Olivier Schwartz: Université de Paris Cité
Sylvie van der Werf: Université de Paris Cité
Nolwenn Jouvenet: Université de Paris Cité
Sébastien Nisole: , Université de Montpellier, CNRS
Marco Vignuzzi: Université de Paris Cité
Ferdinand Roesch: Université de Paris Cité

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identify DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX is sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricts infection. DAXX restricts an early, post-entry step of the SARS-CoV-2 life cycle. DAXX-mediated restriction of SARS-CoV-2 is independent of the SUMOylation pathway but dependent on its D/E domain, also necessary for its protein-folding activity. SARS-CoV-2 infection triggers the re-localization of DAXX to cytoplasmic sites and promotes its degradation. Mechanistically, this process is mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.

Date: 2022
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DOI: 10.1038/s41467-022-30134-9

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