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Analysis of an intracellular signaling from the endoplasmic reticulum to the nucleus

从内质网到细胞核的细胞内信号传导分析

基本信息

批准号：
14037233
负责人：
MORI Kazutoshi
金额：
$ 54.4万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

The endoplamic reticulum (ER) is the place for folding and quality control of newly synthesized secretory and transmembrane proteins. When unfolded proteins are accumulated in the ER under ER stress conditions, the unfolded protein response (UPR), a transcriptional induction program coupled with intracellular signaling from the ER to the nucleus, is activated to maintain the homeostasis of the ER. We have shown that the ATF6 and IRE1-XBP1 pathways play important roles in mammalian UPR. ATF6 is an ER membrane-bound transcription factor activated by proteolysis. On the other hand, XBP1 is a transcription factor whose mRNA is spliced by IRE1. Base on the difference in activation time course and the difference in DNA binding specificity between ATF6 and XBP1, we proposed a time-dependent phase shift in the mammalian UPR, that is shifted from the first phase dealt with endogenous ER chaperones (refolding only), to the second phase dealt with ER chaperones induced by the ATF6 pathway(refolding only), and to the third phase dealt with ER chaperones and ERAD components induced by the IRE1-XBP1 pathway (refolding plus degradation), depending on quality or quantity of unfolded proteins accumulated in the ER.The ER is expanded in professional secretory cells such as plasma cells which is specialized for synthesis and secretion of antibody. We found that overexpression of XBP1 stimulates synthesis of phosphatidylcholine and phosphatidylethanolamine, major components of the ER membrane, and indicated that XBP1 is a key factor connecting quality control of proteins with organelle biogenesis.

内质网是新合成的分泌蛋白和跨膜蛋白折叠和质量控制的场所。当未折叠蛋白在ER应激条件下在ER中积累时，未折叠蛋白应答（UPR），一种与从ER到细胞核的细胞内信号传导偶联的转录诱导程序，被激活以维持ER的稳态。我们已经证明ATF 6和IRE 1-XBP 1通路在哺乳动物UPR中起重要作用。ATF 6是一种通过蛋白水解激活的ER膜结合转录因子。另一方面，XBP 1是一种转录因子，其mRNA被IRE 1剪接。基于ATF 6和XBP 1激活时程的差异和DNA结合特异性的差异，我们提出了哺乳动物UPR的一个时间依赖性相移，即从内源性ER伴侣处理的第一阶段移动（仅重折叠），到第二阶段处理由ATF 6途径诱导的ER分子伴侣（仅重折叠），并进入第三阶段处理由IRE 1-XBP 1途径诱导的ER分子伴侣和ERAD组分（重折叠加降解），这取决于ER中积累的未折叠蛋白质的质量或数量。ER在专门的分泌细胞如浆细胞中扩增，浆细胞专门用于合成和分泌蛋白质。抗体的我们发现，过度表达的XBP 1刺激合成的磷脂酰胆碱和磷脂酰乙醇胺，ER膜的主要成分，并表明，XBP 1是一个关键因素连接质量控制的蛋白质与细胞器的生物合成。