Correcting the Cystic Fibrosis Disease Mutant, A455E CFTR

Cystic fibrosis is caused by more than 1000 mutations, the most common being the Delta F508 mutation. These mutations have been divided into five classes [1], with Delta F508 CFTR in class II. Here we have studied the class V mutation A455E. We report that the mature and immature bands of A455E are rapidly degraded primarily by proteasomes; the short protein half-life of this mutant therefore resembles that of Delta F508 CFTR. A455E could be rescued by treatment of the cells with proteasome inhibitors. Furthermore, co-transfection of A455E with the truncation mutant Delta 264 CFTR also rescued the mature C band, indicating that A455E can be rescued by transcomplementation. We found that Delta 264 CFTR bound to A455E, forming a bimolecular complex. Treatment with the compound correctors C3 and C4 also rescued A455E. These results are significant because they show that although Delta F508 belongs to a different class than A455E, it can be rescued by the same strategies, offering therapeutic promise to patients with Class V mutations.