在展开的蛋白质反应过程中,IRE1信号影响细胞命运
Jonathan H Lin1, Han Li, Douglas Yasumura
1Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA. Jonathan.Lin@ucsf.edu
Science (New York, N.Y.)
|November 10, 2007
概括
持续的内质网膜 (ER) 压力有利于PERK信号传递,促进细胞死亡. 维持 IRE1 信号增强了细胞生存,揭示了展开蛋白质反应 (UPR) 中的一个关键机制.
科学领域:
- 细胞生物学 细胞生物学
- 在ER应力压力的分子机制.
- 展开的蛋白质响应 (UPR) 信号通路
背景情况:
- 细胞内膜网膜 (ER) 的压力触发了展开的蛋白质反应 (UPR),以管理错误折叠的蛋白质.
- UPR包括三个主要分支:IRE1,PERK和ATF6,可以促进细胞存活或细胞亡.
- 通过UPR信号来决定细胞命运 (生存与细胞亡) 的机制仍然不清楚.
研究的目的:
- 调查UPR如何在持续的ER压力下整合亲生存和亲亡信号.
- 确定UPR分支信号的持续时间在细胞命运决定中的作用.
- 探索这些发现在细胞和动物模式的视网膜炎的相关性.
主要方法:
- 在持续ER压力下的人类细胞中分析UPR分支活动 (IRE1,PERK,ATF6).
- 操纵IRE1信号持续时间以评估其对细胞存活的影响.
- 来自动物模型的光受体细胞中发现的发现的验证与突变的罗多普辛.
主要成果:
- 持续的ER压力导致IRE1和ATF6活动的减弱.
- 包括翻译抑制和Chop诱导在内的PERK信号持续存在.
- 人工维持IRE1活动促进了细胞存活.
- 关键发现在视网膜炎的动物模型中得到复制.
结论:
- UPR分支信号的持续时间对于确定ER应激后的细胞命运至关重要.
- 持续的PERK信号传递有助于细胞死亡,而持续的IRE1信号传递有助于生存.
- 这些发现提供了有关视网膜色素炎相关的ER压力诱导细胞死亡机制的见解.
相关概念视频
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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01:32Export of Misfolded Proteins out of the ER
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