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

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 relocalization 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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03707111
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Submitted on : Tuesday, June 28, 2022 - 11:48:18 AM
Last modification on : Thursday, September 1, 2022 - 5:02:06 PM

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Alice Mac Kain, Ghizlane Maarifi, Sophie-Marie Aicher, Nathalie Arhel, Artem Baidaliuk, et al.. Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen. Nature Communications, Nature Publishing Group, 2022, 13, 13 p. ⟨10.1038/s41467-022-30134-9⟩. ⟨pasteur-03707111v2⟩

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