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 process through a pyroglutamate (pGlu)-dependent association with misfolded ΔF508 CFTR. QPCT-dependent pGlu modification promotes the association of PDIA4 with mutant CFTR within the endoplasmic reticulum (ER) quality control machinery, whereas inhibition of QPCT disrupts this interaction, relieving ER retention and enabling a fraction of ΔF508 CFTR to reach the cell surface.

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR ). Though most people with CF have one or two copies of the ΔF508 m...

Read the full paper: Altered functional interactions between CFTR disease mutants ΔF508 and G551D and the protein kinase A catalytic subunit

<span><b>Rationale:</b> Elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) was shown to be safe and efficacious in children 6 through 11 years of age with cystic fibrosis (CF) and at least one <i>F508...

Council approved Resolution F508 to extend the CDBG consortium agreement for three years; staff said the agreement leverages CDBG dollars across jurisdictions and legal review flagged compliance items that staff will confirm before external reporting.

Cystic fibrosis (CF) arises from CFTR mutations, which result in defective ion transport and multisystem pathology. Here, the authors identify a QPCT-PDIA4 pathway that promotes ER retention of misfolded CFTR. QPCT inhibition disrupts the PDIA4-CFTR interaction and restores trafficking and function of &#916;F508 and N1303K CFTR variants.