This article is a Preprint
Preprints are preliminary research reports that have not been certified by peer review. They should not be relied on to guide clinical practice or health-related behavior and should not be reported in news media as established information.
Preprints posted online allow authors to receive rapid feedback and the entire scientific community can appraise the work for themselves and respond appropriately. Those comments are posted alongside the preprints for anyone to read them and serve as a post publication assessment.
SARS-CoV-2 protein encoded by ORF8 contains a histone mimic that disrupts chromatin regulation (preprint)
researchsquare; 2020.
Preprint
in English
| PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-137433.v1
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 novel 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 two critical histone 3 sites containing an ARKS motif. Orf8 expression in cells disrupts multiple critical histone post-translational modifications (PTMs) while Orf8 lacking this histone mimic motif does not. Orf8 binds to numerous histone-associated proteins and to DNA, and is itself acetylated within the histone mimic site. Importantly, SARS-CoV-2 infection of multiple susceptible cell types causes the same global changes of histone post-translational modifications that are disrupted by Orf8 expression; these include induced pluripotent stem cell-derived alveolar type 2 cells (iAT2) and cardiomyocytes (iCM) and postmortem patient lung tissue. These findings demonstrate a novel function for the poorly understood SARS-CoV-2 ORF8 encoded protein and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Notably, this work provides a potential mechanism for emerging findings from human patients indicating that ORF8 deletion results in less severe illness and describes a potentially druggable pathway that may contribute to the virulence of SARS-CoV-2.
Full text:
Available
Collection:
Preprints
Database:
PREPRINT-RESEARCHSQUARE
Main subject:
Adenocarcinoma, Bronchiolo-Alveolar
/
COVID-19
Language:
English
Year:
2020
Document Type:
Preprint
Similar
MEDLINE
...
LILACS
LIS