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dc.contributor.authorZhang, Jiantao
dc.contributor.authorLi, Qi
dc.contributor.authorCruz Cosme, Ruth S
dc.contributor.authorGerzanich, Vladimir
dc.contributor.authorTang, Qiyi
dc.contributor.authorSimard, J Marc
dc.contributor.authorZhao, Richard Y
dc.date.accessioned2022-01-19T14:25:57Z
dc.date.available2022-01-19T14:25:57Z
dc.date.issued2021-11-24
dc.identifier.urihttp://hdl.handle.net/10713/17569
dc.description.abstractTherapeutic inhibition of critical viral functions is important for curtailing coronavirus disease-2019 (COVID-19). We sought to identify antiviral targets through genome-wide characterization of SARS-CoV-2 proteins that are crucial for viral pathogenesis and that cause harmful cytopathic effects. All twenty-nine viral proteins were tested in a fission yeast cell-based system using inducible gene expression. Twelve proteins including eight non-structural proteins (NSP1, NSP3, NSP4, NSP5, NSP6, NSP13, NSP14 and NSP15) and four accessory proteins (ORF3a, ORF6, ORF7a and ORF7b) were identified that altered cellular proliferation and integrity, and induced cell death. Cell death correlated with the activation of cellular oxidative stress. Of the twelve proteins, ORF3a was chosen for further study in mammalian cells. In human pulmonary and kidney epithelial cells, ORF3a induced cellular oxidative stress associated with apoptosis and necrosis, and caused activation of pro-inflammatory response with production of the cytokines TNF-α, IL-6, and IFN-β1, possibly through the activation of NF-κB. To further characterize the mechanism, we tested a natural ORF3a Beta variant, Q57H, and a mutant with deletion of the highly conserved residue, ΔG188. Compared to wild type ORF3a, the ΔG188 variant yielded more robust activation of cellular oxidative stress, cell death, and innate immune response. Since cellular oxidative stress and inflammation contribute to cell death and tissue damage linked to the severity of COVID-19, our findings suggest that ORF3a is a promising, novel therapeutic target against COVID-19.en_US
dc.description.urihttps://doi.org/10.1101/2021.11.23.469747en_US
dc.language.isoenen_US
dc.publisherCold Spring Harbor Laboratoryen_US
dc.relation.ispartofbioRxiv : the Preprint Server for Biologyen_US
dc.subjectORF3aen_US
dc.subjectSARS-CoV-2en_US
dc.subjectSchizosaccharomyces pombeen_US
dc.subjectapoptosis and necrosisen_US
dc.subjectcellular pro-inflammatory responseen_US
dc.subjectfission yeasten_US
dc.subjectoxidative stressen_US
dc.subjectviral therapeutic targeten_US
dc.titleGenome-wide characterization of SARS-CoV-2 cytopathogenic proteins in the search of antiviral targets.en_US
dc.typeArticleen_US
dc.identifier.doi10.1101/2021.11.23.469747
dc.identifier.pmid34845452
dc.source.journaltitlebioRxiv : the preprint server for biology
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States


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