Urano F, Bertolotti A, Ron D
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
J Cell Sci. 2000 Nov;113 Pt 21:3697-702. doi: 10.1242/jcs.113.21.3697.
Genetic analysis of the cellular adaptation to malfolded proteins in the endoplasmic reticulum (the unfolded protein response - UPR) has revealed a novel signaling pathway initiated by activation of IRE1, an ER-resident protein kinase and endonuclease. In yeast, Ire1p activates gene expression by promoting a non-conventional splicing event that converts the mRNA encoding the Hac1p transcription factor from an inefficiently translated inactive mRNA to an actively translated one. Hac1p binds to the promoters of genes encoding chaperones and other targets of the UPR and activates them. Recently, mammalian IRE1 homologues have been identified and their response to ER stress is regulated by binding to the ER chaperone BiP. The mechanisms by which mammalian IRE1 activates gene expression have not been completely characterized and mammalian HAC1 homologues have not been identified. Surprisingly, mammalian IRE1s are able to activate both JUN N-terminal kinases and an alternative ER-stress signaling pathway mediated by the transcription factor ATF6. This indicates that the mammalian UPR is more complex than that found in yeast.
细胞对内质网中错误折叠蛋白的适应性（未折叠蛋白反应-UPR）的遗传分析揭示了一种由内质网驻留蛋白激酶和核酸酶IRE1激活引发的新信号通路。在酵母中，Ire1p通过促进一种非常规剪接事件来激活基因表达，该剪接事件将编码Hac1p转录因子的mRNA从低效翻译的无活性mRNA转变为可有效翻译的mRNA。Hac1p与编码伴侣蛋白及UPR其他靶标的基因启动子结合并激活它们。最近，已鉴定出哺乳动物IRE1同源物，其对内质网应激的反应通过与内质网伴侣蛋白BiP结合来调节。哺乳动物IRE1激活基因表达的机制尚未完全阐明，且尚未鉴定出哺乳动物HAC1同源物。令人惊讶的是，哺乳动物IRE1能够激活JUN N端激酶以及由转录因子ATF6介导的另一条内质网应激信号通路。这表明哺乳动物的UPR比酵母中的更为复杂。
