Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia
Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia
复制标题
DOI：
10.1172/jci96273
复制
发表时间：
2019-08-01
影响因子：
15.9
通讯作者：
Ziady, Assem G.
中科院分区：
文献类型：
--
作者：
Borcherding, Dana C.;Siefert, Matthew E.;Ziady, Assem G.
囊性纤维化（CF）是一种多器官进行性遗传性疾病，由功能性囊性纤维化跨膜传导调节因子（CFTR）通道缺失引起。以前，我们确定了一个显着的功能障碍，在CF细胞和模型小鼠的转录因子核因子E2相关因子-2（Nrf 2），氧化还原平衡和炎症信号的主要调节。在这里，我们报告了批准的F508 del CFTR校正剂VX 809和VX 661通过邻近连接测定、免疫沉淀和免疫荧光恢复了CF人原代支气管上皮中减少的Nrf 2功能和与CFTR的共定位，与CFTR校正一致。F508 del CFTR校正剂诱导Nrf 2核转位、Nrf 2依赖性荧光素酶活性和靶基因的转录激活。VX 809/VX 661对Nrf 2功能的拯救依赖于F508 del的显著校正，并且通过抑制校正的通道功能或CFTR或F508 del CFTR的高水平shRNA敲低而被阻断。从机制上讲，F508 del CFTR调节恢复了Nrf 2磷酸化及其与共激活因子CREB结合蛋白（CBP）的相互作用。我们的研究结果表明，F508 del CFTR功能的充分调节可纠正CF中的Nrf 2功能障碍。
Cystic fibrosis (CF) is a multiorgan progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. Previously, we identified a significant dysfunction in CF cells and model mice of the transcription factor nuclear factor E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report that the approved F508del CFTR correctors VX809 and VX661 recover diminished Nrf2 function and colocalization with CFTR in CF human primary bronchial epithelia by proximity ligation assay, immunoprecipitation, and immunofluorescence, concordant with CFTR correction. F508del CFTR correctors induced Nrf2 nuclear translocation, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Rescue of Nrf2 function by VX809/VX661 was dependent on significant correction of F508del and was blocked by inhibition of corrected channel function, or high-level shRNA knockdown of CFTR or F508del CFTR. Mechanistically, F508del CFTR modulation restored Nrf2 phosphorylation and its interaction with the coactivator CREB-binding protein (CBP). Our findings demonstrate that sufficient modulation of F508del CFTR function corrects Nrf2 dysfunction in CF.