MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation
MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation
复制标题
DOI：
10.1152/ajprenal.90482.2008
复制
发表时间：
2008-11-01
影响因子：
4.2
通讯作者：
Sands, Jeff M.
中科院分区：
文献类型：
--
作者：
Chen, Guangping;Huang, Haidong;Sands, Jeff M.
陈刚，黄辉，Frohlich O，杨勇，Klein JD, Price SR, Sands JM。MDM2 E3泛素连接酶介导UT-A1尿素转运蛋白泛素化和降解。[J] .中华医学杂志，2008,31(5):559 - 559。首次发表于2008年9月10日；doi: 10.1152 / ajprenal.90482.2008。-UT-A1是顶质膜上的主要尿素转运蛋白，负责髓内收集管的尿素再吸收。尽管UT-A1的生理功能已被证实，但调控其活性的分子机制尚不清楚。对UT-A1氨基酸序列的分析发现，在UT-A1的胞内大环中存在潜在的MDM2 E3泛素连接酶结合基序，提示UT-A1尿素转运蛋白可能受泛素-蛋白酶体途径的调控。在这里，我们报道UT-A1被蛋白酶体泛素化和降解，而不是溶酶体蛋白水解途径。蛋白酶体活性的抑制导致UT-A1细胞表面积聚，并随之增加尿素运输活性。UT-A1直接与MDM2相互作用；结合位点位于MDM2的nh2端p53结合区。MDM2在体内和体外均介导UT-A1泛素化。MDM2过表达促进UT-A1降解。该机制可能具有重要的生理学意义，因为在肾髓内组织中发现了UT-A1泛素化。泛素-蛋白酶体降解途径为UT-A1调控提供了重要的新机制。
Chen G, Huang H, Frohlich O, Yang Y, Klein JD, Price SR, Sands JM. MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation. Am J Physiol Renal Physiol 295: F1528-F1534, 2008. First published September 10, 2008; doi:10.1152/ajprenal.90482.2008. -UT-A1 is the primary urea transporter in the apical plasma membrane responsible for urea reabsorption in the inner medullary collecting duct. Although the physiological function of UT-A1 has been well established, the molecular mechanisms that regulate its activity are less well understood. Analysis of the UT-A1 amino acid sequence revealed a potential MDM2 E3 ubiquitin ligase-binding motif in the large intracellular loop of UT-A1, suggesting that UT-A1 urea transporter protein may be regulated by the ubiquitin-proteasome pathway. Here, we report that UT-A1 is ubiquitinated and degraded by the proteasome but not the lysosome proteolytic pathway. Inhibition of proteasome activity causes UT-A1 cell surface accumulation and concomitantly increases urea transport activity. UT-A1 interacts directly with MDM2; the binding site is located in the NH2-terminal p53-binding region of MDM2. MDM2 mediates UT-A1 ubiquitination both in vivo and in vitro. Overexpression of MDM2 promotes UT-A1 degradation. The mechanism is likely to be physiologically important as UT-A1 ubiquitination was identified in kidney inner medullary tissue. The ubiquitin-proteasome degradation pathway provides an important novel mechanism for UT-A1 regulation.