Radixin Deficiency Causes Conjugated Hyperbilirubinemia With Loss of Mrp2 From Bile Canalicular Membranes

Nat Genet. 2002 Jul;31(3):320-5. doi: 10.1038/ng905. Epub 2002 Jun 17.

Abstract

The ezrin-radixin-moesin (ERM) family of proteins crosslink actin 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 hyperbilirubinemia 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Canaliculi / cytology
  • Bile Canaliculi / metabolism
  • Bile Canaliculi / ultrastructure
  • Blood Proteins / deficiency
  • Blood Proteins / physiology*
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Cells, Cultured
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / physiology*
  • Drug Resistance, Multiple / genetics
  • Glutathione Transferase / metabolism
  • Hyperbilirubinemia / genetics*
  • Hyperbilirubinemia / pathology
  • Liver / metabolism
  • Liver / pathology
  • Membrane Proteins / deficiency
  • Membrane Proteins / physiology*
  • Membrane Transport Proteins*
  • Mice
  • Mice, Knockout
  • Microvilli / ultrastructure
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Mutation
  • Recombinant Proteins / metabolism
  • Time Factors

Substances

  • Blood Proteins
  • Cytoskeletal Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Recombinant Proteins
  • radixin
  • multidrug resistance-associated protein 2
  • Glutathione Transferase