Inhibition of the QPCT-PDIA4 axis rescues ΔF508 and N1303K CFTR in cystic fibrosis.

Abstract

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. Furthermore, inhibition of QPCT also restores the function of the N1303K CFTR mutant, indicating a broader relevance of this pathway in regulating CFTR proteostasis. These findings provide evidence for an ER quality control mechanism governing mutant CFTR fate and suggest potential therapeutic strategies for CFTR mutations that are unresponsive to existing modulators.