Cell 146, 746–760 (2011)

The most common mutation responsible for cystic fibrosis, which is called Δ508-CFTR, results in protein misfolding, retention in the endoplasmic reticulum (ER) and degradation of an otherwise functional channel. Gee et al. report an unconventional trafficking pathway for Δ508 that is dependent upon Golgi reassembly stacking proteins (GRASPs). The authors showed that conditions associated with ER stress resulted in plasma membrane localization of core-glycosylated Δ508 in cultured cells. The authors blocked conventional ER-to-Golgi trafficking pathways by genetic or chemical means, but neither type of manipulation inhibited the surface localization of functional Δ508. GRASPs, which may be involved in the stacking of Golgi cisternae or the linkage of stacks into a continuous ribbon, have recently been shown to mediate unconventional protein transport. The authors found that knockdown of GRASP abolished unconventional trafficking of Δ508-CFTR. Interaction of Δ508-CFTR with GRASP55 as well as phosphorylation of GRASP55 at Ser441 were important for the unconventional pathway. Overexpression of GRASP55 in transgenic mice rescued growth defects and improved the survival of mice harboring the Δ508-CFTR mutation. These data provide insight into an unconventional protein-trafficking pathway and suggest that activating this pathway could be a therapeutic strategy for the treatment of cystic fibrosis.