Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin
Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin
复制标题
DOI：
10.1182/blood-2009-07-232587
复制
发表时间：
2010-02-25
期刊：
影响因子：
20.3
通讯作者：
Moestrup, Soren K.
中科院分区：
文献类型：
--
作者：
Beedholm-Ebsen, Rasmus;van de Wetering, Koen;Moestrup, Soren K.
人类缺乏钴胺素（Cbl，维生素B-12）是血液学和神经系统疾病的一个原因。我们在这里表明，与依赖载体和受体的Cbl细胞输入相反，Cbl的细胞输出是通过“游离”Cbl的跨膜运输发生的。通过细胞基因沉默筛选候选转运体显示，在肠上皮基底外膜和其他细胞中存在的atp结合盒(ABC)-药物转运体ABCC1，别名多药耐药蛋白1 （MRP1）的细胞Cbl外排中起作用。MRP1介导atp依赖性Cbl转运的能力被水泡转运实验证实，MRP1在哺乳动物Cbl稳态中的生理作用被MRP1靶向破坏的敲除小鼠表型所表明。这些动物的血浆和储存器官肝脏和肾脏中的Cbl浓度降低。相反，Cbl在这些小鼠的肠道末端积累，表明由于上皮基底外侧Cbl外排较低，导致功能性吸收不良。这种Cbl输出机制的鉴定现在可以描绘出从食物到身体细胞的Cbl运输的连贯途径。(血。2010;115:1632 - 1639)
Cobalamin (Cbl, vitamin B-12) deficiency in humans is a cause of hematologic and neurologic disorders. We show here that the cellular export of Cbl, in contrast to the carrier- and receptor-dependent cellular import of Cbl, occurs by transmembrane transport of "free" Cbl. Screening of candidate transporters by cellular gene silencing showed a role in cellular Cbl efflux of the ATP-binding cassette (ABC)-drug transporter, ABCC1, alias multidrug resistance protein 1 (MRP1), which is present in the basolateral membrane of intestinal epithelium and in other cells. The ability of MRP1 to mediate ATP-dependent Cbl transport was confirmed by vesicular transport experiments, and a physiologic role of MRP1 in mammalian Cbl homeostasis is indicated by the phenotype of knockout mice with targeted disruption of MRP1. These animals have a reduced concentration of Cbl in plasma and in the storage organs liver and kidney. In contrast, Cbl accumulates in the terminal part of the intestine of these mice, suggesting a functional malabsorption because of a lower epithelial basolateral Cbl efflux. The identification of this Cbl export mechanism now allows the delineation of a coherent pathway for Cbl trafficking from food to the body cells. (Blood. 2010;115:1632-1639)