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 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.
【초록키워드】 COVID-19, Treatment, eQTL, Comorbidity, RNA, Protein, viability, Genome-wide association study, Viral RNA, RNA polymerase, Calu-3 cell, expression, SARS-CoV-2 replication, association, cellular, Interaction, Analysis, SARS-CoV-2 proteins, host-virus interactions, Safe, therapeutic target, nonsense mutation, higher risk, increased expression, components, host protein, protein expression, loci, valuable resource, polymerase, SARS-CoV-2 viral infection, risk loci, effective, human RNA, PROTECT, identify, examined, form, reduced, demonstrated, interact, New, EXOSC2, the SARS-CoV-2, with COVID-19, 【제목키워드】 COVID-19, expression, SARS-CoV-2 replication, PROTECT, impede, EXOSC2,