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. 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.
Kikuchi
Shojiro
S
Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Hata
Masaki
M
Fukumoto
Kanehisa
K
Yamane
Yukari
Y
Matsui
Takeshi
T
Tamura
Atsushi
A
Yonemura
Shigenobu
S
Yamagishi
Hisakazu
H
Keppler
Dietrich
D
Tsukita
Shoichiro
S
Tsukita
Sachiko
S
D000818:Animals; D001648:Bile Canaliculi / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D001798:Blood Proteins / Q000172:deficiency / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000502:physiology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000648:ultrastructure; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009154:Mutation; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors
D001798:Blood Proteins; D003598:Cytoskeletal Proteins; D005982:Glutathione Transferase; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins; C000715087:ABCC2 protein, human; C071776:radixin