@article{2412cdc8c3c24c1a89ea46dc96534729,
title = "Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia",
abstract = "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.",
author = "Borcherding, {Dana C.} and Siefert, {Matthew E.} and Songbai Lin and John Brewington and Hesham Sadek and Clancy, {John P.} and Plafker, {Scott M.} and Ziady, {Assem G.}",
note = "Funding Information: We thank the CCHMC CF RDP Translational Studies Core for providing primary airway epithelial cells. Provision of primary cells to our sources was by Scott Randell at the University of North Carolina and was supported by grants from the Cystic Fibrosis Foundation (BOUCHE15R0) and NIH (DK065988). We also thank the CCHMC Confocal Imaging Core, directed by Matthew Kofron, for its help with confocal imaging techniques and analysis. We also thank the Case Western Reserve University Cystic Fibrosis Mouse Models Core for providing CF mouse tissues. Gail M. Macke provided assistance with histology. Rhonda Szczesniak at CCHMC aided with statistical analyses. Changsuk Moon and Anjaparavanda P. Naren at CCHMC provided technical advice on the proximity ligation assay. Technical edits to the manuscript and fact checking were provided by Katye M. Fichter of FichterScript LLC. This work was supported by the National Heart, Lung, and Blood Institute (1R01HL109362-01 to AGZ). Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",
year = "2019",
month = aug,
day = "1",
doi = "10.1172/JCI96273",
language = "English (US)",
volume = "129",
pages = "3448--3463",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",
}