Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death
Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death
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DOI：
10.1074/jbc.m203412200
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发表时间：
2002-09-20
影响因子：
4.8
通讯作者：
Nomura, Y
中科院分区：
文献类型：
--
作者：
Ko, HS;Uehara, T;Nomura, Y
几种应激蛋白（例如热休克蛋白和葡萄糖调节蛋白）的上调参与对环境应激的耐受。此前，我们发现星形胶质细胞中蛋白质二硫键异构酶（PDI）在缺氧/脑缺血时特异性上调。此外，该基因在神经元中的过度表达可以防止缺氧/脑缺血引起的细胞凋亡。为了解决 PDI 的详细功能，我们使用酵母双杂交系统筛选了与 PDI 相互作用的蛋白质。我们在此报道 PDI 与泛素相互作用，泛素具有泛素样结构域和泛素相关结构域。有趣的是，神经胶质细胞缺氧时泛素也会上调，其时间过程与 PDI 诱导的时间过程相似。在缺氧处理的神经胶质细胞中，内源性泛素和 PDI 几乎完全共定位，表明泛素是一种内质网相关蛋白。该基因在神经细胞中的过度表达会显着抑制缺氧引发的 DNA 断裂，但不会显着抑制一氧化氮或十字孢菌素诱导的 DNA 断裂。此外，泛素能够减弱缺氧引起的 CHOP 诱导。这些观察结果表明，泛素与 PDI 一起作为 CHOP 介导的细胞死亡的调节蛋白具有关键功能，因此这些蛋白的上调可能导致神经胶质细胞获得对缺血应激的耐受性。
Up-regulation of several stress proteins such as heat-shock proteins and glucose-regulated proteins participate in tolerance against environmental stress. Previously, we found that protein-disulfide isomerase (PDI) is specifically up-regulated in response to hypoxia/brain ischemia in astrocytes. In addition, the overexpression of this gene into neurons protects against apoptotic cell death induced by hypoxia/brain ischemia. To address the detailed function of PDI, we screened for proteins that interact with PDI using the yeast two-hybrid system. We report here that PDI interacts with ubiquilin, which has a ubiquitin-like domain and a ubiquitin-associated domain. Interestingly, ubiquilin is also up-regulated in response to hypoxia in glial cells with a time course similar to that of PDI induction. In hypoxia-treated glial cells, the endogenous ubiquilin and PDI were almost completely co-localized, suggesting that ubiquilin is an endoplasmic reticulum-associated protein. Overexpression of this gene in neuronal cells resulted in significant inhibition of the DNA fragmentation triggered by hypoxia, but not that induced by nitric oxide or staurosporine. Moreover, ubiquilin has the ability to attenuate CHOP induction by hypoxia. These observations suggested that ubiquilin together with PDI have critical functions as regulatory proteins for CHOP-mediated cell death, and therefore up-regulation of these proteins may result in acquisition of tolerance against ischemic stress in glial cells.