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

Mac Kain, A.; Maarifi, G.; Aicher, S.-M.; Arhel, N.; Baidaliuk, A.; Vallet, T.; Tran, Q. D.; Hardy, A.; Chazal, M.; Porrot, F.; Ohainle, M.; Carlson-Stevermer, J.; Oki, J.; Holden, K.; Simon-Loriere, E.; Bruel, T.; Schwartz, O.; Jouvenet, N.; Nisole, S.; Vignuzzi, M.; Roesch, F.

doi:10.1101/2021.05.06.442916

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bioRxiv · 10.1101/2021.05.06.442916

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

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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 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 and SARS-CoV replication in human cells. Basal expression of DAXX was sufficient to limit the replication of SARS-CoV-2, 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 and promoted its degradation. Mechanistically, this process was 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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Mac Kain, A., Maarifi, G., Aicher, S.-M., Arhel, N., Baidaliuk, A., Vallet, T., Tran, Q. D., Hardy, A., Chazal, M., Porrot, F., Ohainle, M., Carlson-Stevermer, J., Oki, J., Holden, K., Simon-Loriere, E., Bruel, T., Schwartz, O., Jouvenet, N., Nisole, S., Vignuzzi, M., Roesch, F.. 2021-05-06. Identification of DAXX As A Restriction Factor Of SARS-CoV-2 Through A CRISPR/Cas9 Screen. https://doi.org/10.1101/2021.05.06.442916

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