Human HRD1 protects against ER stress-induced apoptosis through ER-associated degradation
Human HRD1 protects against ER stress-induced apoptosis through ER-associated degradation
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DOI：
10.1016/s0014-5793(02)03660-8
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发表时间：
2002-12-04
期刊：
影响因子：
3.5
通讯作者：
Nomura, Y
中科院分区：
文献类型：
--
作者：
Kaneko, M;Ishiguro, M;Nomura, Y
损伤内质网（ER）功能的应激导致内质网中未折叠蛋白的积累。在这些条件下，诱导参与防止未折叠蛋白质积累的多种基因的表达。酵母Hrd1p是一种内质网应激诱导的内质网膜蛋白，作为一种具有RING指基序的泛素连接酶（E3），在内质网中蛋白质的泛素化中发挥作用。我们在这里报告的识别和表征的人类同源酵母Hrd1p。预测的结构是高度保守的从酵母到人类。事实上，人URD1定位于ER并泛素化其底物。此外，发现人HRD 1通过ER应激转导子IRE 1和ATF 6被ER应激上调。有趣的是，293细胞稳定表达野生型HRD 1，但不是C329S突变体，提供了ER应激诱导的细胞凋亡的阻力。这些结果表明，HRD 1的生产上调，以防止ER应激诱导的细胞凋亡，通过降解未折叠的蛋白积累在ER。(C)2002年欧洲生物化学学会联合会。由Elsevier Science B.V.出版，版权所有。
Stresses that impair the function of the endoplasmic reticulum (ER) lead to an accumulation of unfolded protein in the ER. Under these conditions, the expression of a variety of genes involved in preventing the accumulation of the unfolded proteins is induced. Yeast Hrd1p is an ER stress-inducible ER membrane protein that acts as a ubiquitin ligase (E3) with a RING finger motif and plays a role in the ubiquitination of proteins in the ER. We report here the identification and characterization of a human homolog to yeast Hrd1p. The predicted structures are highly conserved from yeast to humans. Indeed, human URD1 was localized to the ER and ubiquitinated its substrates. Furthermore, it was found that human HRD1 was up-regulated by ER stress via IRE1 and ATF6, which are ER stress transducers. Interestingly, 293 cells stably expressing wild-type HRD1, but not the C329S mutant, afforded resistance to ER stress-induced apoptosis. These results suggest that the production of HRD1 is up-regulated to protect against ER stress-induced apoptosis by degrading unfolded proteins accumulated in the ER. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.