PXD034379 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | SARS-CoV-2 protein encoded by ORF8 contains a histone mimic, disrupts chromatin regulation, and enhances replication |
Description | 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 cell’s 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. |
HostingRepository | PRIDE |
AnnounceDate | 2024-04-02 |
AnnouncementXML | Submission_2024-04-02_06:45:23.337.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Joseph A Cesare |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive HF; Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-06-06 07:21:17 | ID requested | |
1 | 2022-07-22 11:19:58 | announced | |
⏵ 2 | 2024-04-02 06:45:24 | announced | 2024-04-02: Updated project metadata. |
Publication List
Kee J, Thudium S, Renner DM, Glastad K, Palozola K, Zhang Z, Li Y, Lan Y, Cesare J, Poleshko A, Kiseleva AA, Truitt R, Cardenas-Diaz FL, Zhang X, Xie X, Kotton DN, Alysandratos KD, Epstein JA, Shi PY, Yang W, Morrisey E, Garcia BA, Berger SL, Weiss SR, Korb E, Author Correction: SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature, 614(7949):E44(2023) [pubmed] |
10.1038/s41586-023-05764-8; |
Keyword List
ProteomeXchange project tag: Sars-cov-2, Covid-19 |
submitter keyword: Epigenetics, infectious disease, SARS-CoV-2 |
Contact List
Benjamin A. Garcia |
contact affiliation | Raymond H. Wittcoff Distinguished Professor and Head Department of Biochemistry and Molecular Biophysics Washington University School of Medicine St. Louis, MO 63110 United States of America |
contact email | bagarcia@wustl.edu |
lab head | |
Joseph A Cesare |
contact affiliation | University of Pennsylvania |
contact email | josephacesare@gmail.com |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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[ - ]
- PRIDE
- PXD034379
- Label: PRIDE project
- Name: SARS-CoV-2 protein encoded by ORF8 contains a histone mimic, disrupts chromatin regulation, and enhances replication