∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.

Abstract

SummaryDeletion of phenylalanine 508 of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is the major cause of Cystic Fibrosis (CF), one of the most common inherited childhood diseases. The mutated CFTR anion channel is not fully glycosylated and shows minimal activity in bronchial epithelial cells of CF patients. Low temperature or inhibition of histone deacetylases (HDACi) can partially rescue ΔF508 CFTR cellular processing defects and function. A favorable change of ΔF508 CFTR protein-protein interactions was proposed as mechanism of rescue, however CFTR interactome dynamics during temperature-shift and HDACi rescue are unknown. Here, we report the first comprehensive analysis of the wt and ΔF508 CFTR interactome and its dynamics during temperature shift and HDACi. By using a novel deep proteomic analysis method (CoPIT), we identified 638 individual high-confidence CFTR interactors and discovered a mutation-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promoted enhanced CFTR channel function in primary CF epithelia or which were critical for normal CFTR biogenesis. Our results demonstrate that global remodeling of ΔF508 CFTR interactions is crucial for rescue, and provide comprehensive insight into the molecular disease mechanisms of CF caused by deletion of F508.