Cloning of mammalian Ire1 reveals diversity in the ER stress responses
Cloning of mammalian Ire1 reveals diversity in the ER stress responses
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DOI：
10.1093/emboj/17.19.5708
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发表时间：
1998-10-01
期刊：
影响因子：
11.4
通讯作者：
Ron, D
中科院分区：
文献类型：
--
作者：
Wang, XZ;Harding, HP;Ron, D
细胞改变其基因表达模式，以响应来自内质网（ER）的应激信号。这种反应的充分表征的方面包括编码蛋白伴侣和其他ER驻留蛋白的基因的激活，并且在哺乳动物和酵母之间是保守的。然而，在哺乳动物细胞中，ER应激也激活其他途径，包括转录因子CHOP/GADD 153及其下游靶基因的表达。ER应激也与程序性细胞死亡的发展有关，这是CHOP发挥重要作用的一种现象。在这里，我们报告的酵母IRE 1，一个重要的上游组成部分的ER压力反应在酵母的小鼠同源克隆。哺乳动物Ire 1位于ER膜上，其在哺乳动物Tell中的过表达激活内源性ER伴侣GRP 78/BiP和CHOP编码基因。Ire 1的显性负性形式的过表达阻断响应于衣霉素处理诱导的ER应激的GRP 78/BiP和CHOP的诱导。鼠Ire 1的过表达也导致转染细胞中程序性细胞死亡的发展。这些结果表明，一个单一的上游组件，Ire 1，在哺乳动物细胞的ER应激反应的多个方面发挥作用。
Cells modify their gene expression pattern in response to stress signals emanating from the endoplasmic reticulum (ER). The well-characterized aspect of this response consists of the activation of genes that encode protein chaperones and other ER resident proteins, and is conserved between mammals and yeast. In mammalian cells, however, ER stress also activates other pathways, including the expression of the transcription factor CHOP/GADD153 and its downstream target genes. ER stress is also linked to the development of programmed cell death, a phenomenon in which CHOP plays an important role. Here we report on the cloning of a murine homolog of yeast IRE1, an essential upstream component of the ER stress-response in yeast. The mammalian Ire1 is located in the ER membrane and its over-expression in mammalian tells activates both the endogenous ER chaperone GRP78/BiP and CHOP-encoding genes. Over-expression of a dominant-negative form of Ire1 blocks the induction of GRP78/BiP and CHOP in response to the ER stress induced by tunicamycin treatment. Over-expression of murine Ire1 also leads to the development of programmed cell death in transfected cells. These results indicate that a single upstream component, Ire1, plays a role in multiple facets of the ER stress-response in mammalian cells.