PXD034379-2

PXD034379 is an original dataset announced via ProteomeXchange.

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

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.

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;

ProteomeXchange project tag: Sars-cov-2, Covid-19

submitter keyword: Epigenetics, infectious disease, SARS-CoV-2

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

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PRIDE project URI

• PRIDE
  1. PXD034379
     1. Label: PRIDE project
     2. Name: SARS-CoV-2 protein encoded by ORF8 contains a histone mimic, disrupts chromatin regulation, and enhances replication