RAB10 Interacts with ABCB4 and Regulates Its Intracellular Traffic

ABCB4 (ATP-binding cassette subfamily B member 4) is an ABC transporter expressed at the canalicular membrane of hepatocytes where it ensures phosphatidylcholine secretion into bile. Genetic variations of ABCB4 are associated with several rare cholestatic diseases. The available treatments are not e...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-06, Vol.22 (13), p.7087
Main Authors: Ben Saad, Amel, Vauthier, Virginie, Lapalus, Martine, Mareux, Elodie, Bennana, Evangéline, Durand-Schneider, Anne-Marie, Bruneau, Alix, Delaunay, Jean-Louis, Gonzales, Emmanuel, Housset, Chantal, Aït-Slimane, Tounsia, Guillonneau, François, Jacquemin, Emmanuel, Falguières, Thomas
Format: Article
Language:English
Subjects:
ABC transporter
Antibodies
Bile
bile secretion
Experiments
Gallbladder diseases
Genetic diversity
Hepatocytes
Human health and pathology
Hypotheses
Hépatology and Gastroenterology
Immunoprecipitation
Intracellular
intracellular traffic
Lecithin
Life Sciences
Liver diseases
Mass spectrometry
Mass spectroscopy
MDR3
Membranes
Molecular modelling
Phosphatidylcholine
Plasma
Proteins
RAB GTPase
Scientific imaging
Transplantation
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Summary:ABCB4 (ATP-binding cassette subfamily B member 4) is an ABC transporter expressed at the canalicular membrane of hepatocytes where it ensures phosphatidylcholine secretion into bile. Genetic variations of ABCB4 are associated with several rare cholestatic diseases. The available treatments are not efficient for a significant proportion of patients with ABCB4-related diseases and liver transplantation is often required. The development of novel therapies requires a deep understanding of the molecular mechanisms regulating ABCB4 expression, intracellular traffic, and function. Using an immunoprecipitation approach combined with mass spectrometry analyses, we have identified the small GTPase RAB10 as a novel molecular partner of ABCB4. Our results indicate that the overexpression of wild type RAB10 or its dominant-active mutant significantly increases the amount of ABCB4 at the plasma membrane expression and its phosphatidylcholine floppase function. Contrariwise, RAB10 silencing induces the intracellular retention of ABCB4 and then indirectly diminishes its secretory function. Taken together, our findings suggest that RAB10 regulates the plasma membrane targeting of ABCB4 and consequently its capacity to mediate phosphatidylcholine secretion.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22137087