Turnbull Emma L, Rosser Meredith F N, Cyr Douglas M
Department of Cell and Developmental Biology, 526 Taylor Hall, Mason Farm Road, UNC-Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
BMC Biochem. 2007 Nov 22;8 Suppl 1(Suppl 1):S11. doi: 10.1186/1471-2091-8-S1-S11.
CF is an inherited autosomal recessive disease whose lethality arises from malfunction of CFTR, a single chloride (Cl-) ion channel protein. CF patients harbor mutations in the CFTR gene that lead to misfolding of the resulting CFTR protein, rendering it inactive and mislocalized. Hundreds of CF-related mutations have been identified, many of which abrogate CFTR folding in the endoplasmic reticulum (ER). More than 70% of patients harbor the DeltaF508 CFTR mutation that causes misfolding of the CFTR proteins. Consequently, mutant CFTR is unable to reach the apical plasma membrane of epithelial cells that line the lungs and gut, and is instead targeted for degradation by the UPS. Proteins located in both the cytoplasm and ER membrane are believed to identify misfolded CFTR for UPS-mediated degradation. The aberrantly folded CFTR protein then undergoes polyubiquitylation, carried out by an E1-E2-E3 ubiquitin ligase system, leading to degradation by the 26S proteasome. This ubiquitin-dependent loss of misfolded CFTR protein can be inhibited by the application of 'corrector' drugs that aid CFTR folding, shielding it from the UPS machinery. Corrector molecules elevate cellular CFTR protein levels by protecting the protein from degradation and aiding folding, promoting its maturation and localization to the apical plasma membrane. Combinatory application of corrector drugs with activator molecules that enhance CFTR Cl- ion channel activity offers significant potential for treatment of CF patients. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
囊性纤维化（CF）是一种常染色体隐性遗传病，其致死性源于囊性纤维化跨膜传导调节因子（CFTR）功能异常，CFTR是一种单一的氯离子（Cl-）离子通道蛋白。CF患者的CFTR基因发生突变，导致所产生的CFTR蛋白错误折叠，使其失去活性并定位错误。已鉴定出数百种与CF相关的突变，其中许多突变会消除内质网（ER）中CFTR的折叠。超过70%的患者携带DeltaF508 CFTR突变，该突变导致CFTR蛋白错误折叠。因此，突变的CFTR无法到达肺和肠道内衬上皮细胞的顶端质膜，而是被蛋白酶体靶向降解。位于细胞质和内质网膜中的蛋白质被认为可识别错误折叠的CFTR以便进行蛋白酶体介导的降解。异常折叠的CFTR蛋白随后会经历多聚泛素化，这是由E1-E2-E3泛素连接酶系统进行的，导致被26S蛋白酶体降解。应用有助于CFTR折叠的“校正”药物可抑制这种错误折叠的CFTR蛋白的泛素依赖性损失，使其免受蛋白酶体机制的影响。校正分子通过保护蛋白质不被降解并帮助其折叠，促进其成熟并定位到顶端质膜，从而提高细胞内CFTR蛋白水平。校正药物与增强CFTR Cl-离子通道活性的激活分子联合应用为治疗CF患者提供了巨大的潜力。出版历史：转载自Current BioData的靶向蛋白质数据库（TPdb；http://www.targetedproteinsdb.com）。
