The Effects of IRE1, ATF6, and PERK Signaling on adRP-Linked Rhodopsins
The Effects of IRE1, ATF6, and PERK Signaling on adRP-Linked Rhodopsins
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DOI：
10.1007/978-1-4614-3209-8_83
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发表时间：
2014-01-01
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影响因子：
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通讯作者：
Lin, Jonathan H.
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文献类型：
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作者：
Chiang, Wei-Chieh Jerry;Lin, Jonathan H.
与色素性视网膜炎（RP）相关的视紫红质基因的许多突变导致视紫红质错误折叠。表达错误折叠视紫红质的杆状光感受器细胞最终死亡。确定防止视紫红质错误折叠或去除不可修复的错误折叠视紫红质的机制可以提供新的治疗策略。IRE1、ATF6和PERK信号通路统称为未折叠蛋白反应（UPR），它们调节内质网的功能，负责视紫红质等膜蛋白的精确折叠。我们使用化学和遗传方法选择性地激活IRE1， ATF6或PERK信号通路，并分析了它们对RP相关的突变视紫红质的影响。我们发现人工IRE1和ATF6信号都促进了突变型视紫质的降解，而对野生型视紫质的影响较小。此外，IRE1和ATF6信号优先降低聚集视紫红质水平。相比之下，PERK信号降低了野生型和突变型视紫红质的水平。这些研究表明IRE1、ATF6或PERK的激活可以阻止突变的视紫红质在细胞中积累。此外，IRE1或ATF6的激活可以选择性地从细胞中去除聚集或突变的视紫红质，并可能有助于治疗与视紫红质蛋白错误折叠相关的RP。
Many mutations in rhodopsin gene linked to retinitis pigmentosa (RP) cause rhodopsin misfolding. Rod photoreceptor cells expressing misfolded rhodopsin eventually die. Identifying mechanisms to prevent rhodopsin misfolding or to remove irreparably misfolded rhodopsin could provide new therapeutic strategies. IRE1, ATF6, and PERK signaling pathways, collectively called the unfolded protein response (UPR), regulate the functions of endoplasmic reticulum, responsible for accurate folding of membrane proteins such as rhodopsin. We used chemical and genetic approaches to selectively activate IRE1, ATF6, or PERK signaling pathways one at a time and analyzed their effects on mutant rhodopsin linked to RP. We found that both artificial IRE1 and ATF6 signaling promoted the degradation of mutant rhodopsin with lesser effects on wild-type rhodopsin. Furthermore, IRE1 and ATF6 signaling preferentially reduced levels of aggregated rhodopsins. By contrast, PERK signaling reduced levels of wild-type and mutant rhodopsin. These studies indicate that activation of either IRE1, ATF6, or PERK prevents mutant rhodopsin from accumulating in the cells. In addition, activation of IRE1 or ATF6 can selectively remove aggregated or mutant rhodopsin from the cells and may be useful in treating RP associated with rhodopsin protein misfolding.