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Effect of CFTR correctors on the traffic and the function of intracellularly retained ABCB4 variants
Author(s) -
Ben Saad Amel,
Vauthier Virginie,
Tóth Ágota,
Janaszkiewicz Angelika,
DurandSchneider AnneMarie,
Bruneau Alix,
Delaunay JeanLouis,
Lapalus Martine,
Mareux Elodie,
Garcin Isabelle,
Gonzales Emmanuel,
Housset Chantal,
AïtSlimane Tounsia,
Jacquemin Emmanuel,
Di Meo Florent,
Falguières Thomas
Publication year - 2021
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14839
Subject(s) - in silico , cystic fibrosis transmembrane conductance regulator , transporter , microbiology and biotechnology , cholestasis , atp binding cassette transporter , secretion , transmembrane protein , biology , biochemistry , bone canaliculus , chemistry , gene , receptor , anatomy , endocrinology
A bstract Background & aim ABCB4 is expressed at the canalicular membrane of hepatocytes. This ATP‐binding cassette (ABC) transporter is responsible for the secretion of phosphatidylcholine into bile canaliculi. Missense genetic variations of ABCB4 are correlated with several rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). In a repurposing strategy to correct intracellularly retained ABCB4 variants, we tested 16 compounds previously validated as cystic fibrosis transmembrane conductance regulator (CFTR) correctors. Methods The maturation, intracellular localization and activity of intracellularly retained ABCB4 variants were analyzed in cell models after treatment with CFTR correctors. In addition, in silico molecular docking calculations were performed to test the potential interaction of CFTR correctors with ABCB4. Results We observed that the correctors C10, C13, and C17, as well as the combinations of C3 + C18 and C4 + C18, allowed the rescue of maturation and canalicular localization of four distinct traffic‐defective ABCB4 variants. However, such treatments did not permit a rescue of the phosphatidylcholine secretion activity of these defective variants and were also inhibitory of the activity of wild type ABCB4. In silico molecular docking analyses suggest that these CFTR correctors might directly interact with transmembrane domains and/or ATP‐binding sites of the transporter. Conclusion Our results illustrate the uncoupling between the traffic and the activity of ABCB4 because the same molecules can rescue the traffic of defective variants while they inhibit the secretion activity of the transporter. We expect that this study will help to design new pharmacological tools with potential clinical interest.