tetano
Editor, Senior Moderator
Nature
. 2022 Oct 5.
doi: 10.1038/s41586-022-05282-z. Online ahead of print.
SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry
John Kee[SUP] 1 2 [/SUP], Samuel Thudium[SUP] #[/SUP][SUP] 1 2 [/SUP], David M Renner[SUP] #[/SUP][SUP] 3 4 [/SUP], Karl Glastad[SUP] #[/SUP][SUP] 2 5 [/SUP], Katherine Palozola[SUP] 1 2 [/SUP], Zhen Zhang[SUP] 2 5 [/SUP], Yize Li[SUP] 3 4 [/SUP], Yemin Lan[SUP] 2 [/SUP], Joseph Cesare[SUP] 2 6 [/SUP], Andrey Poleshko[SUP] 5 [/SUP], Anna A Kiseleva[SUP] 5 7 8 [/SUP], Rachel Truitt[SUP] 9 [/SUP], Fabian L Cardenas-Diaz[SUP] 9 10 [/SUP], Xianwen Zhang[SUP] 11 [/SUP], Xuping Xie[SUP] 11 [/SUP], Darrell N Kotton[SUP] 12 13 [/SUP], Konstantinos D Alysandratos[SUP] 12 13 [/SUP], Johnathan A Epstein[SUP] 5 7 8 9 [/SUP], Pei-Yong Shi[SUP] 11 [/SUP], Wenli Yang[SUP] 9 [/SUP], Edward Morrisey[SUP] 9 10 [/SUP], Benjamin A Garcia[SUP] 2 6 [/SUP], Shelley L Berger[SUP] 2 5 14 [/SUP], Susan R Weiss[SUP] 3 4 [/SUP], Erica Korb[SUP] 15 16 [/SUP]
Affiliations
Abstract
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 responses[SUP]1-3[/SUP]. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins[SUP]4-8[/SUP], particularly those containing post-translational modifications required for transcriptional regulation[SUP]9-11[/SUP]. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation[SUP]12-14[/SUP]. 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.
. 2022 Oct 5.
doi: 10.1038/s41586-022-05282-z. Online ahead of print.
SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry
John Kee[SUP] 1 2 [/SUP], Samuel Thudium[SUP] #[/SUP][SUP] 1 2 [/SUP], David M Renner[SUP] #[/SUP][SUP] 3 4 [/SUP], Karl Glastad[SUP] #[/SUP][SUP] 2 5 [/SUP], Katherine Palozola[SUP] 1 2 [/SUP], Zhen Zhang[SUP] 2 5 [/SUP], Yize Li[SUP] 3 4 [/SUP], Yemin Lan[SUP] 2 [/SUP], Joseph Cesare[SUP] 2 6 [/SUP], Andrey Poleshko[SUP] 5 [/SUP], Anna A Kiseleva[SUP] 5 7 8 [/SUP], Rachel Truitt[SUP] 9 [/SUP], Fabian L Cardenas-Diaz[SUP] 9 10 [/SUP], Xianwen Zhang[SUP] 11 [/SUP], Xuping Xie[SUP] 11 [/SUP], Darrell N Kotton[SUP] 12 13 [/SUP], Konstantinos D Alysandratos[SUP] 12 13 [/SUP], Johnathan A Epstein[SUP] 5 7 8 9 [/SUP], Pei-Yong Shi[SUP] 11 [/SUP], Wenli Yang[SUP] 9 [/SUP], Edward Morrisey[SUP] 9 10 [/SUP], Benjamin A Garcia[SUP] 2 6 [/SUP], Shelley L Berger[SUP] 2 5 14 [/SUP], Susan R Weiss[SUP] 3 4 [/SUP], Erica Korb[SUP] 15 16 [/SUP]
Affiliations
- PMID: 36198800
- DOI: 10.1038/s41586-022-05282-z
Abstract
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 responses[SUP]1-3[/SUP]. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins[SUP]4-8[/SUP], particularly those containing post-translational modifications required for transcriptional regulation[SUP]9-11[/SUP]. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation[SUP]12-14[/SUP]. 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.