Abstract
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.
Highlights
ABCB4 (ATP-binding cassette subfamily B member 4), named MDR3 (MultiDrugResistance 3), is one of the main biliary transporters [1]
We found that the overexpression of RAB10-wild type (WT) or its constitutively active mutant increases ABCB4 membrane expression and function, whereas RAB10 silencing attenuates ABCB4 cell surface expression, as well as its PC secretion function
Despite the important role played by ABCB4 in bile secretion, little is known about the molecular mechanisms regulating its expression, intracellular traffic, and function
Summary
Resistance 3), is one of the main biliary transporters [1] It is expressed at the canalicular membrane of hepatocytes where it mediates phosphatidylcholine (PC) secretion into bile [2]. While treatment with ursodeoxycholic acid remains efficient for the majority of patients with milder forms of ABCB4-related diseases, this is not the case for patients with PFIC3, the most severe form of these diseases, who most often require liver transplantation [6,7], stressing the unmet need for new therapeutic options. In the frame of personalized medicine, new targeted pharmacotherapies for ABCB4-related diseases have been proposed from in vitro studies and include the potentiator Ivacaftor/VX-770 as well as structural analogues of roscovitine [8,9]. In order to better characterize and understand the mode of action of new therapies, a better understanding of the molecular mechanisms regulating ABCB4 traffic and function is required
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