Department of Ophthalmology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America ; Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS One. 2014 Jan 8;9(1):e85183. doi: 10.1371/journal.pone.0085183. eCollection 2014.
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.
囊性纤维化是由超过 1000 种突变引起的，最常见的是ΔF508 突变。这些突变已被分为五类[1]，ΔF508 CFTR 属于第二类。在这里，我们研究了第五类突变 A455E。我们报告说，A455E 的成熟和不成熟条带主要通过蛋白酶体迅速降解；因此，这种突变体的短蛋白半衰期类似于 ΔF508 CFTR。用蛋白酶体抑制剂处理细胞可以挽救 A455E。此外，A455E 与截断突变体 Δ264 CFTR 的共转染也挽救了成熟的 C 带，表明 A455E 可以通过转互补来挽救。我们发现 Δ264 CFTR 与 A455E 结合，形成双分子复合物。用化合物校正剂 C3 和 C4 处理也可以挽救 A455E。这些结果意义重大，因为它们表明，尽管 ΔF508 属于与 A455E 不同的类别，但可以通过相同的策略来挽救，为第五类突变的患者提供了治疗希望。
