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

ABSTRACT: New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic. Genome-wide association studies (GWAS) have identified a number of risk loci but these include co-morbidities 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. We identified lung-specific eQTLs from GTEx (v7) for 332 host proteins which directly interact with SARS-CoV-2 proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed a robust association between increased expression of EXOSC2 and higher risk of clinical COVID-19. EXOSC2 is a component of the RNA exosome and further LC-MS/MS analysis of protein pulldowns demonstrated an interaction between the SARS-CoV-2 RNA polymerase and the majority of RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu3 cells reduced EXOSC2 protein expression, impeded SARS-CoV-2 replication and upregulated OAS genes which have been linked to a successful immune response against SARS-CoV-2. OAS gene expression changes occurred independent of infection, in the absence of significant upregulation of other interferon-stimulated genes (ISGs), and did not coincide with reduced cellular viability. Targeted depletion or functional inhibition of EXOSC2 may be a safe and effective strategy to protect at-risk individuals against clinical COVID-19.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Early Embryonic Cell

SUBMITTER: Mark Collins  

LAB HEAD: Mark Collins

PROVIDER: PXD031611 | Pride | 2022-10-13

REPOSITORIES: Pride