The ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common disease-causing mutation found in people with cystic fibrosis, as, despite being functional, the ΔF508 CFTR protein cannot reach the cell surface. A new study shows that the activation of an unconventional secretion pathway mediated by Golgi reassembly stacking proteins (GRASPs) allows the transport of both this mutant and wild-type CFTR to the plasma membrane (Cell 146, 746–760).

The misfolded ΔF508 CFTR usually remains a core-glycosylated immature form in the endoplasmic reticulum (ER) and cannot be secreted through the Golgi-mediated exocytic pathway. Heon Yung Gee and colleagues showed that this protein reached the membrane after blocking ER-to-Golgi trafficking in vitro. This transport route was mediated by inositol-requiring protein 1 (IRE-1), which activates the unfolded protein response (UPR). Using knockout and overexpression strategies in cultured cells, the authors found that GRASPs were required for this unconventional transport route. Interestingly, GRASP upregulation rescued the mutant CFTR without inducing the ER stress–mediated UPR, but IRE-1 was still needed for the phosphorylation and activity of GRASP. In mice harboring the ΔF508 CFTR mutation, transgenic expression of GRASP rescued the apical expression of the misfolded CFTR and increased survival.

Although rescue of ΔF508 CFTR through GRASP upregulation may be a potential drug strategy to treat cystic fibrosis, it remains to be shown whether other means of GRASP activation can recapitulate this effect in other in vivo models of cystic fibrosis.