Moll, Tobias orcid.org/0000-0001-5928-2514, Odon, Valerie, Harvey, Calum et al. (17 more authors) (2023) Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication. Life Science Alliance, 6 (1). ARTN e202201449. e202201449-e202201449. ISSN 2575-1077
Abstract
New therapeutic targets are a valuable resource for treatment of SARS-CoV-2 viral infection. Genome-wide association studies have identified risk loci associated with COVID-19, but many loci are associated with comorbidities and are not specifictohost–virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of the 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins. Aggregating COVID-19 genome-wide association studies statistics for genespecific eQTLs revealed an association between increased expression of EXOSC2 and higher risk of clinical COVID-19. EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. EXOSC2 is a component of the RNA exosome, and here, LC-MS/MS analysis of protein pulldowns demonstrated interaction between the SARS-CoV-2 RNA polymerase and most of the human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu-3 cells reduced EXOSC2 protein expressionandimpededSARS-CoV-2replicationwithoutimpacting cellular viability. Targeted depletion of EXOSC2 may be a safe and effective strategy to protect against clinical COVID-19.
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Copyright, Publisher and Additional Information: | © 2022 Moll et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). | ||||||||
Keywords: | COVID-19; Chromatography, Liquid; Codon, Nonsense; DNA-Directed RNA Polymerases; Exosome Multienzyme Ribonuclease Complex; Genome-Wide Association Study; Humans; RNA, Viral; RNA-Binding Proteins; SARS-CoV-2; Tandem Mass Spectrometry; Viral Replicase Complex Proteins; Virus Replication | ||||||||
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Institution: | The University of Sheffield | ||||||||
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
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Depositing User: | Symplectic Sheffield | ||||||||
Date Deposited: | 04 Jan 2023 14:27 | ||||||||
Last Modified: | 04 Jan 2023 14:27 | ||||||||
Published Version: | http://dx.doi.org/10.26508/lsa.202201449 | ||||||||
Status: | Published online | ||||||||
Publisher: | Life Science Alliance, LLC | ||||||||
Refereed: | Yes | ||||||||
Identification Number: | https://doi.org/10.26508/lsa.202201449 | ||||||||
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