An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery
An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery
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DOI：
10.1073/pnas.0604816103
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发表时间：
2006-07-25
影响因子：
11.1
通讯作者：
Canessa, Cecilia M.
中科院分区：
文献类型：
--
作者：
Arteaga, Maria Francisca;Wang, Lin;Canessa, Cecilia M.
血清和糖皮质激素激酶1 （Sgk1）调节上皮细胞中的许多离子通道和转运蛋白，并促进细胞在应激条件下的存活。在这项研究中，我们证明了Sgk1是一种短寿命蛋白，受内质网（ER）相关降解系统和内质网亚细胞定位的调节。我们在酵母和哺乳动物细胞中发现了一个疏水基序（残基18-30）作为内质网定位和通过泛素(Ub)/蛋白酶体途径快速降解的信号。基序疏水性的缺失或减少将Sgk1重新分配到细胞质和细胞核中，并显着延长其半衰期。我们确定Ub偶联的UBC6和UBC7以及Ub连接酶HRD1是介导Sgk1降解的er相关的Ub酶；因此，Sgk1已被确定为哺乳动物HRD1的细胞质底物。Sgk1的区隔化控制着Sgk1介导的信号通路的功能和空间特异性，而快速的蛋白质周转提供了一种快速调节Sgk1丰度的手段，以响应不同的激素和外部刺激，增加Sgk1基因的转录。
Serum- and glucocorticoid-incluced kinase 1 (Sgk1) regulates many ion channels and transporters in epithelial cells and promotes cell survival under stress conditions. in this study we demonstrate that Sgk1 is a short-lived protein regulated by the endoplasmic reticulum (ER)-associated degradation system and subcellular localization to the ER. We identified a hydrophobic motif (residues 18-30) as the signal for ER localization and rapid degradation by the ubiquitin (Ub)/proteasome pathway in both yeast and mammalian cells. Deletion or reduction of hydrophobicity of the motif redistributes Sgk1 to the cytosol and nucleus and markedly increases its half-life. We determined that the Ub-conjugating UBC6 and UBC7 and the Ub ligase HRD1 are the ER-associated Ub enzymes that mediate degradation of Sgk1; thus, Sgk1 has been identified as a cytosolic substrate for mammalian HRD1. Compartmentalization of Sgk1 controls the functional and spatial specificities of Sgk1-mediated signaling pathways, whereas rapid protein turnover provides a means to rapidly adjust Sgk1 abundance in response to different hormonal and external stimuli that increase Sgk1 gene transcription.