QPCT-PDIA4 axis inhibition rescues ΔF508 and N1303K CFTR function in cystic fibrosis models

Cystic fibrosis (CF) is a severe genetic disorder caused by mutations in the CFTR gene, leading to defective ion transport and multisystem pathology. The most common mutation, ΔF508, results in misfolded CFTR protein retained in the endoplasmic reticulum (ER). While small-molecule modulators partially restore ΔF508 CFTR function, their efficacy is limited, and mutations like N1303K remain largely refractory to current treatments. There's a critical need for novel mechanisms to overcome ER retention and restore CFTR function for these unresponsive mutations.

Researchers utilized cellular models of cystic fibrosis expressing ΔF508 and N1303K CFTR mutations. They employed integrated molecular and physiological analyses to investigate the role of the glutaminyl-peptide cyclotransferase (QPCT)-PDIA4 axis. The intervention involved inhibiting QPCT activity to observe its impact on CFTR surface expression and functional activity. Control arms likely included untreated mutant cells and potentially cells treated with existing CFTR modulators for comparison, though specific details on doses or experimental groups were not provided in the abstract.

Inhibition of the QPCT-dependent pathway rescued both surface expression and functional activity of ΔF508 CFTR. Molecular analyses identified protein disulfide-isomerase A4 (PDIA4) as a key mediator, associating with misfolded ΔF508 CFTR via a pyroglutamate (pGlu)-dependent mechanism. This QPCT-dependent pGlu modification promotes PDIA4 binding to mutant CFTR within the endoplasmic reticulum (ER) quality control machinery. > Disrupting this interaction through QPCT inhibition relieved ER retention, allowing a fraction of ΔF508 CFTR to reach the cell surface. Importantly, QPCT inhibition also restored the function of the N1303K CFTR mutant, demonstrating broader applicability beyond ΔF508 and suggesting a general role for this pathway in CFTR proteostasis.