A PDZ-Like Motif in the Biliary Transporter ABCB4 Interacts with the Scaffold Protein EBP50 and Regulates ABCB4 Cell Surface Expression

PloS One
Quitterie VenotTounsia Aït-Slimane

Abstract

ABCB4/MDR3, a member of the ABC superfamily, is an ATP-dependent phosphatidylcholine translocator expressed at the canalicular membrane of hepatocytes. Defects in the ABCB4 gene are associated with rare biliary diseases. It is essential to understand the mechanisms of its canalicular membrane expression in particular for the development of new therapies. The stability of several ABC transporters is regulated through their binding to PDZ (PSD95/DglA/ZO-1) domain-containing proteins. ABCB4 protein ends by the sequence glutamine-asparagine-leucine (QNL), which shows some similarity to PDZ-binding motifs. The aim of our study was to assess the potential role of the QNL motif on the surface expression of ABCB4 and to determine if PDZ domain-containing proteins are involved. We found that truncation of the QNL motif decreased the stability of ABCB4 in HepG2-transfected cells. The deleted mutant ABCB4-ΔQNL also displayed accelerated endocytosis. EBP50, a PDZ protein highly expressed in the liver, strongly colocalized and coimmunoprecipitated with ABCB4, and this interaction required the QNL motif. Down-regulation of EBP50 by siRNA or by expression of an EBP50 dominant-negative mutant caused a significant decrease in the level of ABCB4...Continue Reading

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Citations

Nov 2, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jillian L EllisChunyue Yin
Feb 8, 2019·Nature Reviews. Nephrology·Sanjay K Nigam, Kevin T Bush
Dec 7, 2017·Current Medicinal Chemistry·Marcelo G RomaEnrique J Sánchez Pozzi
Mar 7, 2021·International Journal of Molecular Sciences·Amel Ben SaadThomas Falguières
Jul 3, 2021·International Journal of Molecular Sciences·Amel Ben SaadThomas Falguières

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Methods Mentioned

BETA
transfection
transfections
confocal microscopy
protein assay
glycosylation
coimmunoprecipitation

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