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

Mac Kain, AliceAliceMac KainMaarifi, GhizlaneGhizlaneMaarifiAicher, Sophie-MarieSophie-MarieAicherArhel, NathalieNathalieArhelBaidaliuk, ArtemArtemBaidaliukMunier, SandieSandieMunierDonati, FloraFloraDonatiVallet, ThomasThomasValletTran, Quang DinhQuang DinhTranHardy, AlexandraAlexandraHardyChazal, MaximeMaximeChazalPorrot, FrançoiseFrançoisePorrotOhAinle, MollyMollyOhAinleCarlson-Stevermer, JaredJaredCarlson-StevermerOki, JenniferJenniferOkiHolden, KevinKevinHoldenZimmer, GertGertZimmerSimon-Lorière, EtienneEtienneSimon-LorièreBruel, TimothéeTimothéeBruelSchwartz, OlivierOlivierSchwartzvan der Werf, SylvieSylvievan der WerfJouvenet, NolwennNolwennJouvenetNisole, SébastienSébastienNisoleVignuzzi, MarcoMarcoVignuzziRoesch, FerdinandFerdinandRoesch2024-10-092024-10-092022-05-04https://boris-portal.unibe.ch/handle/20.500.12422/70593Interferon 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.en600 - Technology::630 - AgricultureIdentification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen.article10.48350/1697803550846010.1038/s41467-022-30134-9