Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication.

Autor:	Moll T; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Odon V; Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Harvey C; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Collins MO; School of Biosciences, University of Sheffield, Sheffield, UK., Peden A; School of Biosciences, University of Sheffield, Sheffield, UK., Franklin J; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Graves E; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Marshall JN; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Dos Santos Souza C; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Zhang S; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA., Castelli L; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Hautbergue G; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Azzouz M; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Gordon D; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.; Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA., Krogan N; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.; Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, USA.; Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA.; Quantitative Biosciences Institute (QBI) COVID-19 Research Group (QCRG), San Francisco, CA, USA., Ferraiuolo L; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Snyder MP; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA., Shaw PJ; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., Rehwinkel J; Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Cooper-Knock J; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK j.cooper-knock@sheffield.ac.uk.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2022 Oct 14; Vol. 6 (1). Date of Electronic Publication: 2022 Oct 14 (Print Publication: 2023).
DOI:	10.26508/lsa.202201449
Abstrakt:	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 specific to host-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 gene-specific 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 expression and impeded SARS-CoV-2 replication without impacting cellular viability. Targeted depletion of EXOSC2 may be a safe and effective strategy to protect against clinical COVID-19. (© 2022 Moll et al.)
Databáze:	MEDLINE
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