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). 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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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 |
Dates: |
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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) |
Funding Information: | Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/S009566/1 WELLCOME TRUST (THE) 216596/Z/19/Z National Institute for Health Research IS-BRC-1215-20017 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 04 Jan 2023 14:27 |
Last Modified: | 27 Sep 2024 03:20 |
Published Version: | http://dx.doi.org/10.26508/lsa.202201449 |
Status: | Published |
Publisher: | Life Science Alliance, LLC |
Refereed: | Yes |
Identification Number: | 10.26508/lsa.202201449 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:194881 |