Identification of DAXX As A Restriction Factor Of SARS-CoV-2 Through A CRISPR/Cas9 Screen

Kain, Alice Mac; Maarifi, Ghizlane; Aicher, Sophie-Marie; Arhel, Nathalie; Baidaliuk, Artem; Vallet, Thomas; Tran, Quang Dinh; Hardy, Alexandra; Chazal, Maxime; Porrot, Françoise; OhAinle, Molly; Carlson-Stevermer, Jared; Oki, Jennifer; Holden, Kevin; Simon-Lorière, Etienne; Bruel, Timothée; Schwartz, Olivier; Jouvenet, Nolwenn; Nisole, Sébastien; Vignuzzi, Marco; Roesch, Ferdinand

While interferon restricts SARS-CoV-2 replication in cell culture, 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 identified 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 replication in human cells. Basal expression of DAXX was sufficient to limit the replication of the virus, and DAXX over-expression further restricted infection. In contrast with most of its previously described antiviral activities, DAXX-mediated restriction of SARS-CoV-2 was independent of the SUMOylation pathway. SARS-CoV-2 infection triggered the re-localization of DAXX to cytoplasmic sites of viral replication and led to its degradation. Together, these results demonstrate that DAXX is a potent restriction factor for SARS-CoV-2 and that the virus has evolved a mechanism to counteract its action.