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首页> 外文期刊>American Journal of Physiology >Mutually dependent localization of megalin and Dab2 in the renal proximal tubule.
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Mutually dependent localization of megalin and Dab2 in the renal proximal tubule.

机译：肾小管中巨蛋白和Dab2的相互依赖性定位。

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摘要

Disabled-2 (Dab2) is a cytoplasmic adaptor protein that binds to the cytoplasmic tail of the multiligand endocytic receptor megalin, abundantly expressed in renal proximal tubules. Deletion of Dab2 induces a urinary increase in specific plasma proteins such as vitamin D binding protein and retinol binding protein (Morris SM, Tallquist MD, Rock CO, and Cooper JA. EMBO J 21: 1555-1564, 2002). However, the subcellular localization of Dab2 in the renal proximal tubule and its function have not been fully elucidated yet. Here, we report the characterization of Dab2 in the renal proximal tubule. Immunohistocytochemistry revealed colocalization with megalin in coated pits and vesicles but not in dense apical tubules and the brush border. Kidney-specific megalin knockout almost abolished Dab2 staining, indicating that Dab2 subcellular localization requires megalin in the proximal tubule. Reciprocally, knockout of Dab2 led to a redistribution of megalin from endosomes to microvilli. In addition, there was an overall decrease in levels of megalin protein observed by immunoblotting but no decrease in clathrin or alpha-adaptin protein levels or in megalin mRNA. In rat yolk sac epithelial BN16 cells, Dab2 was present apically and colocalized with megalin. Introduction of anti-Dab2 antibody into BN16 cells decreased the internalization of 125I-labeled receptor-associated protein, substantiating the role of Dab2 in megalin-mediated endocytosis. The present study shows that Dab2 is localized in the apical endocytic apparatus of the renal proximal tubule and that this localization requires megalin. Furthermore, the study suggests that the urinary loss of megalin ligands observed in Dab2 knockout mice is caused by suboptimal trafficking of megalin, leading to decreased megalin levels.
机译：Disabled-2（Dab2）是一种胞质衔接蛋白，与多配体内吞受体巨蛋白的胞质尾结合，在肾脏近端小管中大量表达。缺失Dab2诱导尿中特​​定血浆蛋白例如维生素D结合蛋白和视黄醇结合蛋白的尿增加（Morris SM，Tallquist MD，Rock CO，和Cooper JA.EMBO J 21：1555-1564，2002）。但是，Dab2在肾近端小管中的亚细胞定位及其功能尚未完全阐明。在这里，我们报告肾近端小管中Dab2的表征。免疫组化显示与巨蛋白共定位于包被的凹坑和囊泡中，但未在密集的根尖小管和刷状缘中。肾脏特异性巨蛋白敲除几乎消除了Dab2染色，表明Dab2亚细胞定位需要近端小管中的megalin。相反，Dab2的敲除导致巨蛋白从内体到微绒毛的重新分布。此外，通过免疫印迹观察到的巨蛋白蛋白水平总体下降，但网格蛋白或α-适蛋白蛋白水平或巨蛋白mRNA没有下降。在大鼠卵黄囊上皮BN16细胞中，Dab2出现在顶端，并与megalin共定位。将抗Dab2抗体引入BN16细胞可减少125I标记的受体相关蛋白的内在化，从而证实Dab2在巨蛋白介导的内吞作用中的作用。本研究表明，Dab2位于肾脏近端小管的顶端内吞设备中，并且这种定位需要megalin。此外，研究表明，在Dab2基因敲除小鼠中观察到的巨蛋白配体的尿流失是由于巨蛋白的最佳转运所致，导致巨蛋白水平降低。

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