Abstract
Cystic fibrosis is caused by more than 1000 mutations, the most common being the ΔF508 mutation. These mutations have been divided into five classes [1], with ΔF508 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 ΔF508 CFTR. A455E could be rescued by treatment of the cells with proteasome inhibitors. Furthermore, co-transfection of A455E with the truncation mutant Δ264 CFTR also rescued the mature C band, indicating that A455E can be rescued by transcomplementation. We found that Δ264 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 ΔF508 belongs to a different class than A455E, it can be rescued by the same strategies, offering therapeutic promise to patients with Class V mutations.
Highlights
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) [2]
Expression of A455E When we compared the expression of the A455E mutant to that of both wild-type and nF508 CFTR (Fig. 1) by western blotting, we found that the amount of CFTR protein was greatly reduced in the Cos7 cells transfected with the A455E mutant
Transcomplementation of nF508-CFTR by fragments of CFTR has been observed [13,14,17,20,20]. These fragments are themselves extremely efficiently degraded; they bind to DF508 CFTR and improve the maturation from the immature band B to mature band C
Summary
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) [2]. Symptoms of CF include higher-than-normal sweat chloride, thick airway mucus, persistent lung infections, pancreatic enzyme insufficiency, intestinal blockage, and infertility in males [3]. Extensive effort has been made to understand the genotype of CF patients, with over 1000 gene mutations identified far [4] These mutations in the CF gene have been divided into five different classes: Class I mutations result in defective protein production. Class III mutations produce a protein that has defective regulation; the most common is the G551D mutation, which reaches the cell surface but does not conduct chloride [6,7]. Class V mutations affect protein synthesis or splicing, causing less protein to be made One of these class V mutations is A455E
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