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Intracellular transport and molecular chaperone

细胞内运输和分子伴侣

基本信息

批准号：
15390087
负责人：
AOE Tomohiko
金额：
$ 8.45万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390087/
关键词：
endoplasmic reticulum ER stress KDEL receptor Golgi 小胞体ストッレス

项目摘要

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response. The resultant outcomes are cytoprotective, but also pro-apoptotic. ER chaperones and misfolded proteins exit to the secretory pathway and are retrieved to the ER, during which process the KDEL receptor plays a significant role. Using an expression of a mutant KDEL receptor that lacks the ability for ligand recognition, we show that the impairment of retrieval by the KDEL receptor led to a mis-sorting of BiP, an ER chaperone that has a retrieval signal from the early secretory pathway, which induced intense ER stress response and an increase in susceptibility to ER stress in HeLa cells. Furthermore, we show that the ER stress response accompanied the activation of p38 MAP kinases and c-Jun amino-terminal kinases (JNKs) and that the expression of the mutant KDEL receptor suppressed the activation of p38 and JNK1 not JNK2. The effect of the expression of the mutant KDEL receptor was consistent with the effect of a specific inhibitor for p38 MAP kinases, since the inhibitor sensitized HeLa cells to ER stress. We also found that the activation of the KDEL receptor by the ligand induced the phosphorylation of p38 MAP kinases. These results indicate that the KDEL receptor participates in the ER stress response not only by its retrieval ability but also by modulating MAP kinase signalling, which may affect the outcomes of the mammalian ER stress response.

错误折叠的蛋白质在内质网(ER)中堆积，引发内质网应激反应。由此产生的结果是细胞保护，但也促进了细胞凋亡。内质网伴侣蛋白和错误折叠的蛋白进入分泌途径，并被回收到内质网，在此过程中，KDEL受体起着重要的作用。利用缺乏配体识别能力的突变KDEL受体的表达，我们发现KDEL受体的检索障碍导致了Bip的错误排序，Bip是一种具有从早期分泌途径恢复的信号的ER伴侣，它在HeLa细胞中诱导了强烈的ER应激反应，并增加了对ER应激的敏感性。此外，我们还发现，内质网应激反应伴随着p38 MAP激酶和c-Jun氨基末端激酶(JNKs)的激活，而突变的KDEL受体的表达抑制了p38和JNK1的激活，而不是JNK2。突变的KDEL受体的表达与p38 MAP激酶的特异性抑制剂的作用是一致的，因为该抑制剂使HeLa细胞对内质网应激敏感。我们还发现，配体激活KDEL受体诱导了p38 MAP激酶的磷酸化。这些结果表明，KDEL受体不仅通过其修复能力参与内质网应激反应，而且还通过调节MAP激酶信号，这可能影响哺乳动物内质网应激反应的结果。