Bile formation: Do not ignore the role of plasma membrane–cytoskeleton linking proteins

Authors

  • Konstantinos N. Lazaridis M.D.,

    1. Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, MN
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  • Nicholas F. LaRusso M.D.

    1. Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, MN
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  • Editors Hartmut Jaeschke, Little Rock, AR Kevin Mullen, Cleveland, OH Darius Moradpour, Freiburg, Germany

Abstract

The ezrin-radixin-moesin (ERM) family of proteins crosslink ac-tin filaments and integral membrane proteins. Radixin (encoded by Rdx) is the dominant ERM protein in the liver of wildtype mice and is concentrated at bile canalicular membranes (BCMs). Here we show that Rdx(–/–) mice are normal at birth, but their serum concentrations of conjugated bilirubin begin to increase gradually around 4 weeks, and they show mild liver injury after 8 weeks. This phenotype is similar to human conjugated hyperbiliru-binemia in Dubin-Johnson syndrome, which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2), although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 concentrates at BCMs to secrete conjugated bilirubin into bile. In the BCMs of Rdx / mice, Mrp2 is decreased compared with other BCM proteins such as dipeptidyl peptidase IV (CD26) and P-glycoproteins. In vitro binding studies show that radixin associates directly with the car-boxy-terminal cytoplasmic domain of human MRP2. These findings indicate that radixin is required for secretion of conjugated bilirubin through its support of Mrp2 localization at BCMs.

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