A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response
A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response
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DOI：
10.1016/s0092-8674(00)81667-0
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发表时间：
1999-12-23
期刊：
影响因子：
64.5
通讯作者：
Walter, P
中科院分区：
文献类型：
--
作者：
Niwa, M;Sidrauski, C;Walter, P
未折叠蛋白反应(UPR)介导从内质网到细胞核的信号传递。在酵母中，UPR的关键调控步骤是不依赖剪接体的HAC1mRNA的剪接，该剪接体编码UPR特异的转录因子，该剪接由跨膜激酶/内切核酸酶IRE1启动。我们证明了酵母HAC1 mRNA在UPR诱导下在哺乳动物细胞中正确地剪接，哺乳动物的IRE1可以精确地切割两个剪接接头。令人惊讶的是，UPR诱导导致IRE1的蛋白水解性切割，释放包含积累在细胞核中的激酶和核酸酶结构域的片段。在早老素-1基因敲除细胞中，核定位和UPR诱导减少。这些结果表明，UPR的显著特征在真核细胞中是保守的，并且早老素-1控制着哺乳动物细胞中IRE1的蛋白分解。
The unfolded protein response (UPR) mediates signaling from the endoplasmic reticulum to the nucleus. In yeast, a key regulatory step in the UPR is the spliceosome-independent splicing of HAC1 mRNA encoding a UPR-specific transcription factor, which is initiated by the transmembrane kinase/endoribonuclease Ire1. We show that yeast HAC1 mRNA is correctly spliced in mammalian cells upon UPR induction and that mammalian Ire1 can precisely cleave both splice junctions. Surprisingly, UPR induction leads to proteolytic cleavage of Ire1, releasing fragments containing the kinase and nuclease domains that accumulate in the nucleus. Nuclear localization and UPR induction are reduced in presenilin-1 knockout cells. These results suggest that the salient features of the UPR are conserved among eukaryotic cells and that presenilin-1 controls Ire1 proteolysis in mammalian cells.