TY - JOUR
AU - Moll, Tobias
AU - Odon, Valerie
AU - Harvey, Calum
AU - Collins, Mark O.
AU - Peden, Andrew A.
AU - Franklin, John
AU - Graves, Emily
AU - Marshall, Jack N.G.
AU - dos Santos Souza, Cleide
AU - Zhang, Sai
AU - Castelli, Lydia
AU - Hautbergue, Guilliume
AU - Azzouz, Mimoun
AU - Gordon, David E.
AU - Krogan, Nevan J.
AU - Ferraiuolo, Laura
AU - Snyder, Michael P.
AU - Shaw, Pamela J.
AU - Rehwinkel, Jan
AU - Cooper-Knock, Johnathan
PY - 2022
DA - October
TI - Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication
JO - Life Science Alliance
VL - 6
IS - 1
DO - https://doi.org/10.26508/lsa.202201449
AB - 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 ofEXOSC2and 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 withinEXOSC2in 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.
PB - Embopress
UR - https://strathprints.strath.ac.uk/94029/
KW - Coronavirus (COVID-19)
ER