IRE1 signaling affects cell fate during the unfolded protein response
IRE1 signaling affects cell fate during the unfolded protein response
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DOI：
10.1126/science.1146361
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发表时间：
2007-11-09
期刊：
影响因子：
56.9
通讯作者：
Walter, Peter
中科院分区：
文献类型：
--
作者：
Lin, Jonathan H.;Li, Han;Walter, Peter
内质网（ER）应激激活一系列信号通路，统称为未折叠蛋白反应（UPR）。三个UPR分支（IRE1，PERK和ATF6）通过减少错误折叠的蛋白质水平来促进细胞存活。如果ER应激不减轻，UPR信号也促进凋亡性细胞死亡。UPR如何整合其细胞保护和促凋亡输出，以选择生存或死亡细胞的命运是未知的。我们发现，IRE1和ATF6的活动减弱了持续的ER压力在人类细胞。相比之下，PERK信号传导，包括翻译抑制和促凋亡转录调节因子Chop诱导，得以维持。当IRE1活性被人工维持时，细胞存活率提高，这表明ER应激后UPR分支信号传导的持续时间与细胞的生死命运之间存在因果关系。我们在细胞培养研究中的关键发现在视网膜色素变性动物模型中表达突变视紫红质的光感受器中得到了概括。
Endoplasmic reticulum (ER) stress activates a set of signaling pathways, collectively termed the unfolded protein response (UPR). The three UPR branches (IRE1, PERK, and ATF6) promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. How the UPR integrates its cytoprotective and proapoptotic outputs to select between life or death cell fates is unknown. We found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and proapoptotic transcription regulator Chop induction, was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from our studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa.