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

AI Article Synopsis

  • Interferon can limit SARS-CoV-2 replication, but only a few Interferon Stimulated Genes (ISGs) with antiviral properties have been discovered.
  • A CRISPR/Cas9 screening identified DAXX as a potent inhibitor of SARS-CoV-2, showing that its basic expression can restrict virus replication, especially during early infection stages.
  • The study revealed that SARS-CoV-2 triggers DAXX's movement to the cytoplasm and promotes its degradation through mechanisms involving the viral protease PLpro and the proteasome, illustrating a viral strategy to evade DAXX's inhibitory effects.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9068693PMC
http://dx.doi.org/10.1038/s41467-022-30134-9DOI Listing

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