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SARS-CoV-2 variant-specific differences in inhibiting the effects of the PKR-activated integrated stress response
Karolinska Inst, Sweden.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.ORCID iD: 0000-0001-9076-1441
Univ Helsinki, Finland; Umea Univ, Sweden.
2024 (English)In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 339, article id 199271Article in journal (Refereed) Published
Abstract [en]

The integrated stress response (ISR) is a eukaryotic cell pathway that triggers translational arrest and the formation of stress granules (SGs) in response to various stress signals, including those caused by viral infections. The SARS-CoV-2 nucleocapsid protein has been shown to disrupt SGs, but SARS-CoV-2 interactions with other components of the pathway remains poorly characterized. Here, we show that SARS-CoV-2 infection triggers the ISR through activation of the eIF2 alpha-kinase PKR while inhibiting a variety of downstream effects. In line with previous studies, SG formation was efficiently inhibited and the induced eIF2 alpha phosphorylation only minimally contributed to the translational arrest observed in infected cells. Despite ISR activation and translational arrest, expression of the stress-responsive transcription factors ATF4 and CHOP was not induced in SARS-CoV-2 infected cells. Finally, we found variant-specific differences in the activation of the ISR between ancestral SARS-CoV-2 and the Delta and Omicron BA.1 variants in that Delta infection induced weaker PKR activation while Omicron infection induced higher levels of p-eIF2 alpha, and greatly increased SG formation compared to the other variants. Our results suggest that different SARS-CoV-2 variants can affect normal cell functions differently, which can have an impact on pathogenesis and treatment strategies.

Place, publisher, year, edition, pages
ELSEVIER , 2024. Vol. 339, article id 199271
Keywords [en]
SARS-COV-2; Integrated stress response; Stress granules; Translational arrest; SARS-COV-2 variants; Omicron
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-200038DOI: 10.1016/j.virusres.2023.199271ISI: 001127773600001PubMedID: 37979658OAI: oai:DiVA.org:liu-200038DiVA, id: diva2:1827040
Note

Funding Agencies|CIMED; SciLifeLab/KWA

Available from: 2024-01-12 Created: 2024-01-12 Last updated: 2024-11-06

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