Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova, Italy.
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova, Italy.
Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165611. doi: 10.1016/j.bbadis.2019.165611. Epub 2019 Nov 15.
F508del-CFTR, the most common mutation in cystic fibrosis (CF) patients, impairs CFTR trafficking to plasma membrane leading to its premature proteasomal degradation. Several post-translational modifications have been identified on CFTR with multiple roles in stability, localization and channel function, and the possibility to control the enzymes responsible of these modifications has been long considered a potential therapeutic strategy. Protein kinase CK2 has been previously suggested as an important player in regulating CFTR functions and it has been proposed as a pharmacological target in a combinatory therapy to treat CF patients. However, the real implication of CK2 in F508del-CFTR proteostasis, and in particular the hypothesis that its inhibition could be important in CF therapies, is still elusive. Here, by using immortalized cell lines, primary human cells, and knockout cell lines deprived of CK2 subunits, we do not disclose any direct correlation between F508del-CFTR proteostasis and CK2 expression/activity. Rather, our data indicate that the CK2α' catalytic subunit should be preserved rather than inhibited for F508del rescue by the correctors of class-1, such as VX-809, disclosing new important features in CF therapeutic approaches.
F508del-CFTR 是囊性纤维化 (CF) 患者中最常见的突变，它会损害 CFTR 向质膜的转运，导致其过早被蛋白酶体降解。CFTR 上已经鉴定出多种翻译后修饰，这些修饰在稳定性、定位和通道功能中具有多种作用，并且控制这些修饰的酶的可能性一直被认为是一种潜在的治疗策略。蛋白激酶 CK2 先前被认为是调节 CFTR 功能的重要参与者，并且已被提议作为联合治疗 CF 患者的药物靶点。然而，CK2 在 F508del-CFTR 蛋白稳态中的真正作用，特别是其抑制在 CF 治疗中的重要性，仍然难以捉摸。在这里，通过使用永生化细胞系、原代人类细胞和缺乏 CK2 亚基的敲除细胞系，我们没有发现 F508del-CFTR 蛋白稳态与 CK2 表达/活性之间存在任何直接相关性。相反，我们的数据表明，对于第 1 类校正剂（如 VX-809）的 F508del 修复，CK2α'催化亚基应该被保留而不是被抑制，这揭示了 CF 治疗方法的新的重要特征。
