Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes
Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes
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DOI：
10.1038/ng905
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发表时间：
2002-07-01
期刊：
影响因子：
30.8
通讯作者：
Tsukita, S
中科院分区：
文献类型：
--
作者：
Kikuchi, S;Hata, M;Tsukita, S
蛋白质的ezrin-radixin-moesin（ERM）家族交联肌动蛋白丝和整合膜蛋白（1-3）。Radixin（由Rdx编码）是野生型小鼠肝脏中的主要ERM蛋白（4，5），并集中在胆小管膜（BCM）（5）。在这里，我们发现，Rdx（-/-）小鼠出生时是正常的，但它们的血清结合胆红素浓度开始逐渐增加约4周，他们表现出轻度肝损伤后，8周。该表型与Dubin-Johnson综合征中的人结合型高胆红素血症相似（6，7），后者由多药耐药蛋白2（MRP 2，基因符号ABCC 2）突变引起（8-11），尽管该综合征与明显的肝损伤无关。在野生型小鼠中，Mrp 2在BCM处浓缩以将结合胆红素分泌到胆汁中（8、11、12）。在Rdx（-/-）小鼠的BCM中，Mrp 2与其他糖蛋白如二肽基肽酶IV（CD 26）和P-糖蛋白相比降低。体外结合研究表明，radixin与人MRP 2的羧基末端胞质结构域直接相关。这些发现表明，radixin是通过其支持Mrp 2定位在BCM分泌结合胆红素所必需的。
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.