PXD069857

PXD069857 is an original dataset announced via ProteomeXchange.

Title	QPCT-PDIA4 rescues ΔF508 and N1303K CFTR function in cystic fibrosis
Description	Cystic fibrosis (CF) is a genetic disorder caused by CFTR mutations, most commonly ΔF508, leading to defective ion transport and multisystem pathology. Small-molecule modulators partially restore mutant CFTR function, but therapeutic efficacy remains limited, particularly for N1303K mutation refractory to current treatments. Here, we show that inhibition of the glutaminyl-peptide cyclotransferase (QPCT)-dependent pathway rescues both the surface expression and functional activity of ΔF508 CFTR. Integrated molecular and physiological analyses identify protein disulfide-isomerase A4 (PDIA4) as a key mediator of this rescue via its pyroglutamate (pGlu)-dependent interaction with ΔF508 CFTR, which is essential for surface trafficking. Furthermore, inhibition of QPCT also restores the function of the N1303K CFTR mutant, revealing a broader mechanistic relevance of this pathway in correcting CFTR misfolding and trafficking defects. These findings uncover a generalizable mechanism for correcting CFTR folding abnormalities and suggest new therapeutic strategies for mutations unresponsive to existing modulators.
HostingRepository	PRIDE
AnnounceDate	2026-06-05
AnnouncementXML	Submission_2026-06-05_13:49:39.690.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Le Sun
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	2-pyrrolidone-5-carboxylic acid (Glu); 2-pyrrolidone-5-carboxylic acid (Gln); monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-23 18:33:36	ID requested
⏵ 1	2026-06-05 13:49:40	announced

10.1038/S41467-026-74078-W;

submitter keyword: None

John Yates
contact affiliation	the Scripps Research Institute
contact email	jyates@scripps.edu
lab head
Le Sun
contact affiliation	the Scripps Research Institute
contact email	lsun@scripps.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/2026/06/PXD069857

PRIDE project URI

• PRIDE
  1. PXD069857
     1. Label: PRIDE project
     2. Name: QPCT-PDIA4 rescues ΔF508 and N1303K CFTR function in cystic fibrosis