PXD031611-1

PXD031611 is an original dataset announced via ProteomeXchange.

Title	Depletion of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-10-13
AnnouncementXML	Submission_2022-10-13_02:22:01.039.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	MarkCollins
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-11 06:20:20	ID requested
⏵ 1	2022-10-13 02:22:01	announced

Dataset with its publication pending

submitter keyword: SARS-CoV-2, viral replication, EXOSC2

MarkCollins
contact affiliation	School of Biosciences Firth Court, Western Bank University of Sheffield Sheffield, S10 2TN
contact email	mark.collins@sheffield.ac.uk
lab head
MarkCollins
contact affiliation	University of Sheffield
contact email	mark.collins@sheffield.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031611
     1. Label: PRIDE project
     2. Name: Depletion of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication