New drug therapy of the transporter-related diseases through the modulation of membrane trafficking

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Bile salt export pump (BSEP) localizes on canalicular membrane of hepatocytes and mediates biliary excretion of bile salts. BSEP dysfunction attributed to its internalization from hepatocanalicular membrane and subsequent degradation causes intrahepatic cholestasis. At present, no medical therapy for this disease state has been established, because the regulatory mechanism of cell surface expression of BSEP remains to be elucidated. In this study, we explored it focusing on posttranslational machinery and demonstrated that ubiquitination, a posttranslational modification, is an internalization signal of BSEP and that AP2, an adaptor protein for clathrin-mediated endocytosis, is associated with BSEP internazliation through its direct interaction with BSEP.