PXD056702-1

PXD056702 is an original dataset announced via ProteomeXchange.

Title	SARS-CoV-2 nsp15 enhances viral virulence by subverting host antiviral defenses
Description	SARS-CoV-2 encodes numerous virulence factors, yet their precise mechanisms of action remain unknown. We provide evidence that the SARS-CoV-2 non-structural protein 15 (nsp15) enhances viral virulence by suppressing the production of viral double-stranded (dsRNA), a potent inducer of antiviral signaling. The viral variants lacking nsp15 endoribonuclease (EndoU) activity elicited higher innate immune responses and exhibited reduced replication in human stem cell-derived lung type II alveolar epithelial cells, as well as in the lungs of infected hamsters. Consistent with these findings, the catalytically inactive EndoU mutants caused significantly less mortality compared to the wild-type virus in K18-hACE2 mice. Mechanistically, the cells infected with EndoU mutants accumulated more viral double-stranded RNA, causing enhanced stimulation of antiviral pathways. The depletion of proteins involved in viral RNA sensing dampened immune responses to EndoU mutants. These findings indicate that the nsp15 EndoU activity contributes to viral virulence by antagonizing the host antiviral defense mechanisms.
HostingRepository	PRIDE
AnnounceDate	2025-06-30
AnnouncementXML	Submission_2025-06-29_16:35:36.143.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Gordon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-10 15:29:04	ID requested
⏵ 1	2025-06-29 16:35:37	announced

Caobi A, Su CM, Beusch CM, Kenney D, Darling TL, Feng S, Semaan M, Wacquiez A, Sanders NL, Tully ES, Chen DY, Evdokimova M, Ding Z, Jones D, Alysandratos KD, Mizgerd JP, Kirchdoerfer RN, Kotton DN, Douam F, Crossland NA, Boon ACM, Gordon DE, Baker SC, Saeed M, SARS-CoV-2 nsp15 enhances viral virulence by subverting host antiviral defenses. Proc Natl Acad Sci U S A, 122(24):e2426528122(2025) [pubmed]

10.1073/pnas.2426528122;

submitter keyword: nsp15,SARS-CoV-2

Mohsan Saeed
contact affiliation	Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA
contact email	msaeed1@bu.edu
lab head
David Gordon
contact affiliation	Emory University
contact email	david.ezra.gordon@emory.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/06/PXD056702

PRIDE project URI

• PRIDE
  1. PXD056702
     1. Label: PRIDE project
     2. Name: SARS-CoV-2 nsp15 enhances viral virulence by subverting host antiviral defenses