Department of Pediatrics & Institute of NanoBiotechnology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Curr Mol Med. 2012 Aug;12(7):860-71. doi: 10.2174/156652412801318773.
Protein homeostasis (proteostasis) generates and maintains individual proteins in their folded and functional-competent states. The components of the cellular proteostasis machinery also dictate the functional lifetime of a protein by constantly regulating its conformation, concentration and subcellular location. The autosomal recessive disease cystic fibrosis (CF) is caused by a proteostasis-defect in CF transmembrane conductance regulator (CFTR). The most common CF mutation leading to this proteostasis-defect is the deletion of a phenylalanine residue at position 508 (ΔF508) of the CFTR protein. This ΔF508-CFTR protein is prone to aberrant folding, increased ER-associated degradation, atypical intracellular trafficking and reduced stability at the apical membrane. This ΔF508-CF proteostasis-defect leads to an obstructive lung disease characterized by impaired ion transport in airway epithelial cells, mucus buildup in air space and chronic airway inflammation. We assess here whether correcting the underlying defect in ΔF508-CFTR protein processing using therapeutic proteostasis regulators can treat chronic CF lung disease. As a proof of concept, recent studies support that the selective modulation of mutant-CFTR proteostasis may offer promising therapies to reverse chronic CF lung disease.
蛋白质动态平衡（proteostasis）生成并维持蛋白质处于折叠和功能完备的状态。细胞蛋白质动态平衡机制的组成部分还通过不断调节蛋白质的构象、浓度和亚细胞位置来决定蛋白质的功能寿命。常染色体隐性遗传疾病囊性纤维化（CF）是由 CF 跨膜电导调节因子（CFTR）的蛋白质动态平衡缺陷引起的。导致这种蛋白质动态平衡缺陷的最常见 CF 突变是 CFTR 蛋白第 508 位苯丙氨酸残基缺失（ΔF508）。这种 ΔF508-CFTR 蛋白易于发生异常折叠、内质网相关降解增加、非典型细胞内运输和顶端膜稳定性降低。这种 ΔF508-CF 蛋白质动态平衡缺陷导致阻塞性肺疾病，其特征是气道上皮细胞中的离子转运受损、空气空间中黏液积聚和慢性气道炎症。在这里，我们评估使用治疗性蛋白质动态平衡调节剂纠正 ΔF508-CFTR 蛋白加工中的潜在缺陷是否可以治疗慢性 CF 肺部疾病。作为概念验证，最近的研究支持选择性调节突变型 CFTR 蛋白质动态平衡可能为逆转慢性 CF 肺部疾病提供有前途的治疗方法。
