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PXD034379

PXD034379 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleSARS-CoV-2 protein encoded by ORF8 contains a histone mimic, disrupts chromatin regulation, and enhances replication
DescriptionSARS-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.
HostingRepositoryPRIDE
AnnounceDate2022-07-22
AnnouncementXMLSubmission_2022-07-22_11:19:57.794.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterJoseph A Cesare
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListacetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF; Q Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-06-06 07:21:17ID requested
12022-07-22 11:19:58announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Epigenetics, infectious disease, SARS-CoV-2
Contact List
Benjamin A. Garcia
contact affiliationRaymond 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 emailbagarcia@wustl.edu
lab head
Joseph A Cesare
contact affiliationUniversity of Pennsylvania
contact emailjosephacesare@gmail.com
dataset submitter
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