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

Journal article

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

Authors: Moll, T; Odon, V; Harvey, C; Collins, MO; Peden, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cold Spring Harbor Laboratory Press
• Journal: Life Science Alliance
• Volume: 6
• Issue: 1
• Pages: e202201449-e202201449
• Publication date: 2022-10-14
• DOI: 10.26508/lsa.202201449
• EISSN: 2575-1077
• ISSN: 2575-1077
• Language: English
• Keywords: Biology; RNA; Genome; Genetics; Gene expression; Polymerase; Virus; Gene; Computational biology; Viral replication; Virology