TY - JOUR
T1 - SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry
AU - Kee, John
AU - Thudium, Samuel
AU - Renner, David M.
AU - Glastad, Karl
AU - Palozola, Katherine
AU - Zhang, Zhen
AU - Li, Yize
AU - Lan, Yemin
AU - Cesare, Joseph
AU - Poleshko, Andrey
AU - Kiseleva, Anna A.
AU - Truitt, Rachel
AU - Cardenas-Diaz, Fabian L.
AU - Zhang, Xianwen
AU - Xie, Xuping
AU - Kotton, Darrell N.
AU - Alysandratos, Konstantinos D.
AU - Epstein, Johnathan A.
AU - Shi, Pei Yong
AU - Yang, Wenli
AU - Morrisey, Edward
AU - Garcia, Benjamin A.
AU - Berger, Shelley L.
AU - Weiss, Susan R.
AU - Korb, Erica
N1 - Funding Information:
We thank and acknowledge M. Weitzman for feedback and suggestions, A. Stout for microscopy support, C. Comar for viral infections, R. Jain and P. Shaw for protocols, M. Feldman and K. Montone for providing patient samples, and S. Wolf and P. Korb for supervision and support. J.K., S.T., E.K. and research were supported by the Penn Center for Coronavirus and Other Emerging Pathogens and the Dean’s Innovation Fund from the Perelman School of Medicine at the University of Pennsylvania. E.K. was supported by the Sloan Research Fellowship, the Klingenstein-Simons Fellowship, the NARSAD Young Investigator Award and NIH grants R00MH111836 and 1DP2MH129985. Viral work was supported by NIH grant RO1AI140442 supplement for SARS-CoV-2 and funds from the Penn Center for Coronavirus Research and Other Emerging Pathogens. D.M.R. was supported in part by T32AI055400. A.P., A.A.K. and J.A.E. were supported by NIH grant R35HL140018. R.T. and W.Y. were supported in part by institutional funds from the University of Pennsylvania Perelman School of Medicine to the iPSC Core. iPSC cell line generation and sharing were supported by NIH grants NO175N92020C00005 and U01TR001810. Mass spectrometry was supported by AI118891. P.-Y.S. was supported by NIH grants HHSN272201600013C, U01AI151801 and U19AI171413 and by awards from the Sealy Smith Foundation, the Kleberg Foundation, the John S. Dunn Foundation, the Amon G. Carter Foundation, the Gillson Longenbaugh Foundation and the Summerfield Robert Foundation.
Funding Information:
The laboratory of P.-Y.S. has received funding support in sponsored research agreements from Pfizer, Gilead, Novartis, Merck, GSK, IGM Biosciences and Atea Pharmaceuticals. P.-Y.S. is a member of the scientific advisory boards of AbImmune and is founder of FlaviTech. S.R.W. is on the scientific advisory board of Ocugen and Immunome.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/10/13
Y1 - 2022/10/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85139440484&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05282-z
DO - 10.1038/s41586-022-05282-z
M3 - Article
C2 - 36198800
AN - SCOPUS:85139440484
SN - 0028-0836
VL - 610
SP - 381
EP - 388
JO - Nature
JF - Nature
IS - 7931
ER -