Abstract：
Cystic Fibrosis (CF) is a genetic disease caused by mutations in CFTR gene expressing the anion selective channel CFTR located at the plasma membrane of different epithelial cells. The most commonly investigated variant causing CF is F508del. This mutation leads to structural defects in the CFTR protein, which are recognized by the endoplasmic reticulum (ER) quality control system. As a result, the protein is retained in the ER and degraded via the ubiquitin-proteasome pathway. Although blocking ubiquitination to stabilize the CFTR protein has long been considered a potential pharmacological approach in CF, progress in this area has been relatively slow. Currently, no compounds targeting this pathway have entered clinical trials for CF. On the other hand, the emergence of Orkambi initially, and notably the subsequent introduction of Trikafta/Kaftrio, have demonstrated the effectiveness of molecular chaperone-based therapies for patients carrying the F508del variant and even showed efficacy against other variants. These treatments directly target the CFTR variant protein without interfering with cell signaling pathways. This review discusses the limits and potential future of targeting protein ubiquitination in CF.
摘要：
囊性纤维化(CF)是由表达位于不同上皮细胞质膜的阴离子选择性通道CFTR的CFTR基因突变引起的遗传性疾病。引起CF的最常见的变体是F508del。这种突变导致CFTR蛋白的结构缺陷，内质网（ER）质量控制系统认可。因此,蛋白质保留在ER中并通过泛素-蛋白酶体途径降解。尽管阻断泛素化以稳定CFTR蛋白一直被认为是CF中潜在的药理学方法，这方面的进展相对缓慢。目前,尚无针对该途径的化合物进入CF的临床试验.另一方面,最初Orkambi的出现，特别是随后引入的Trikafta/Kaftrio，已经证明了基于分子伴侣的治疗对携带F508del变体的患者的有效性，甚至显示了对其他变体的有效性。这些治疗直接靶向CFTR变体蛋白而不干扰细胞信号传导途径。这篇综述讨论了在CF中靶向蛋白质泛素化的局限性和潜在前景。
