The role of the UPS in cystic fibrosis.
The role of the UPS in cystic fibrosis.
复制标题
DOI：
10.1186/1471-2091-8-s1-s11
复制
发表时间：
2007-11-22
期刊：
影响因子：
--
通讯作者：
Cyr DM
中科院分区：
文献类型：
--
作者：
Turnbull EL;Rosser MF;Cyr DM
CF是一种遗传性常染色体隐性遗传病，其致死率是由单氯离子通道蛋白CFTR功能障碍引起的。CF患者携带CFTR基因突变，导致CFTR蛋白错误折叠，使其失活和定位错误。数以百计的cf相关突变已被确定，其中许多在内质网（ER）中取消了CFTR折叠。超过70%的患者携带ΔF508 CFTR突变，导致CFTR蛋白错误折叠。因此，突变型CFTR无法到达肺和肠道上皮细胞的顶质膜，而是被UPS降解的目标。位于细胞质和内质网膜中的蛋白质被认为可以识别错误折叠的CFTR以进行ups介导的降解。异常折叠的CFTR蛋白随后由E1-E2-E3泛素连接酶系统进行多泛素化，导致26S蛋白酶体降解。这种泛素依赖性的错误折叠的CFTR蛋白的损失可以通过应用“校正”药物来抑制，这些药物可以帮助CFTR折叠，保护它免受UPS机器的影响。校正分子通过保护CFTR蛋白免受降解和帮助折叠，促进其成熟和定位到根尖质膜来提高细胞CFTR蛋白水平。校正药物与激活剂分子联合应用，增强CFTR Cl-离子通道活性，为CF患者的治疗提供了巨大的潜力。发表历史：转载自Current BioData的Targeted Proteins数据库（TPdb）。
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 ΔF508 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; ).