SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication

Kee, J.; Thudium, S.; Renner, D.; Glastad, K.; Palozola, K.; Zhang, Z.; Li, Y.; Cesare, J.; Lan, Y.; Truitt, R.; Cardenas-Diaz, F. L.; Kotton, D. N.; Alysandratos, K. D.; Zhang, X.; Xie, X.; Shi, P.-Y.; Yang, W.; Morrisey, E.; Garcia, B. A.; Berger, S. L.; Weiss, S. R.; Korb, E.

doi:10.1101/2021.11.10.468057

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bioRxiv · 10.1101/2021.11.10.468057

SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication

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Abstract

SARS-CoV-2 emerged in China at the end of 2019 and caused the global pandemic of COVID-19, a disease with high morbidity and mortality. While our understanding of this new virus is rapidly increasing, gaps remain in our understanding of how SARS-CoV-2 can effectively suppress host cell antiviral responses. Recent work on other viruses has demonstrated a novel mechanism through which viral proteins can mimic critical regions of human histone proteins. Histone proteins are responsible for governing genome accessibility and their precise regulation is critical for a cells ability to control transcription and respond to viral threats. Here, we show that the protein encoded by ORF8 (Orf8) in SARS-CoV-2 functions as a histone mimic of the ARKS motif in histone 3. Orf8 is associated with chromatin, binds to numerous histone-associated proteins, and is itself acetylated within the histone mimic site. Orf8 expression in cells disrupts multiple critical histone post-translational modifications (PTMs) including H3K9ac, H3K9me3, and H3K27me3 and promotes chromatin compaction while Orf8 lacking the histone mimic motif does not. Further, SARS-CoV-2 infection in human cell lines and postmortem patient lung tissue cause these same disruptions to chromatin. However, deletion of the Orf8 gene from SARS-CoV-2 largely blocks its ability to disrupt host-cell chromatin indicating that Orf8 is responsible for these effects. Finally, deletion of the ORF8 gene affects the host-cell transcriptional response to SARS-CoV-2 infection in multiple cell types and decreases the replication of SARS-CoV-2 in human induced pluripotent stem cell-derived lung alveolar type 2 (iAT2) pulmonary cells. These findings demonstrate a novel function for the poorly understood ORF8-encoded protein and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Finally, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

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Kee, J., Thudium, S., Renner, D., Glastad, K., Palozola, K., Zhang, Z., Li, Y., Cesare, J., Lan, Y., Truitt, R., Cardenas-Diaz, F. L., Kotton, D. N., Alysandratos, K. D., Zhang, X., Xie, X., Shi, P.-Y., Yang, W., Morrisey, E., Garcia, B. A., Berger, S. L., Weiss, S. R., Korb, E.. 2021-11-11. SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication. https://doi.org/10.1101/2021.11.10.468057

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