SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry

Nature. 2022 Oct;610(7931):381-388. doi: 10.1038/s41586-022-05282-z. Epub 2022 Oct 5.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1-3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4-8, particularly those containing post-translational modifications required for transcriptional regulation9-11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12-14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

MeSH terms

  • COVID-19* / genetics
  • COVID-19* / metabolism
  • COVID-19* / virology
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly
  • Epigenesis, Genetic*
  • Epigenome / genetics
  • Histones* / chemistry
  • Histones* / metabolism
  • Host Microbial Interactions*
  • Humans
  • Molecular Mimicry*
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / metabolism
  • SARS-CoV-2* / pathogenicity
  • Viral Proteins* / chemistry
  • Viral Proteins* / genetics
  • Viral Proteins* / metabolism


  • Chromatin
  • Histones
  • ORF8 protein, SARS-CoV-2
  • Viral Proteins