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

• Published in: Life science alliance Vol. 6; no. 1; p. e202201449
• Main Authors: Moll, Tobias, Odon, Valerie, Harvey, Calum, Collins, Mark O, Peden, Andrew, Franklin, John, Graves, Emily, Marshall, Jack Ng, Dos Santos Souza, Cleide, Zhang, Sai, Castelli, Lydia, Hautbergue, Guillaume, Azzouz, Mimoun, Gordon, David, Krogan, Nevan, Ferraiuolo, Laura, Snyder, Michael P, Shaw, Pamela J, Rehwinkel, Jan, Cooper-Knock, Johnathan
• Format: Journal Article
• Language: English
• Published: United States Life Science Alliance LLC 01.01.2023
• Subjects: Chromatography, Liquid; Codon, Nonsense; COVID-19 - genetics; DNA-Directed RNA Polymerases - genetics; Exosome Multienzyme Ribonuclease Complex - genetics; Genome-Wide Association Study; Humans; RNA, Viral - metabolism; RNA-Binding Proteins - genetics; SARS-CoV-2 - genetics; Tandem Mass Spectrometry; Viral Replicase Complex Proteins; Virus Replication - genetics
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202201449

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 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 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.