Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes

The ezrin-radixin-moesin (ERM) family of proteins crosslink actin filaments and integral membrane proteins(1-3). Radixin (encoded by Rdx) is the dominant ERM protein in the liver of wildtype mice(4,5) and is concentrated at bile canalicular membranes (BCMs)(5). 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 hyperbilirubinemia in Dubin-Johnson syndrome(6,7), which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2)(8-11), although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 concentrates at BCMs to secrete conjugated bilirubin into bile(8,11,12). 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 carboxy-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.