Orchestrating the unfolded protein response in health and disease.
Orchestrating the unfolded protein response in health and disease.
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DOI：
10.1172/jci16886
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发表时间：
2002-11
期刊：
影响因子：
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通讯作者：
R. Kaufman
中科院分区：
文献类型：
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作者：
R. Kaufman
已经采用了多种方法来确定UPR信号成分，它们的功能和生理作用。酵母遗传学允许定义基本内质网应激信号通路。在高等真核生物中同源和平行信号通路的鉴定已经产生了细胞用来感知和补偿内质网过载和应激的机制框架。几种内质网应激信号分子的高水平组织特异性表达模式表明胰腺和肠道是需要UPR来维持生理功能的器官。upr诱导的基因表达分析表明，蛋白质降解是减少内质网中未折叠蛋白积累压力的必要条件。在确定UPR功能及其与疾病的相关性方面取得的主要进展来自于模式生物中UPR信号成分的突变和人类突变的确定。尽管取得了巨大进展，但我们对普遍定期审议途径的认识仍然不完整。进一步的研究有望扩大我们对内质网应激如何影响其他细胞信号通路的理解。当关键成分被缺失或其他类型的突变操纵时，了解普遍定期审议是如何变化的，这将是非常令人兴奋和有益的。此外，尽管目前已知内质网中未折叠蛋白的积累与多种疾病的发病机制有关，但针对这些事件的治疗方法仍然很少。随着对蛋白质折叠过程的进一步了解，用化学伴侣进行药物干预以促进正确折叠变得可行，正如苯丁酸钠对Δ508 CFTR的观察（见Gelman和Kopito， this Perspective series, ref. 53）。未来的干预应考虑激活UPR的不同亚通路或适当蛋白伴侣的过表达，如胞质HSP70的J结构域的过表达，它抑制了苍蝇的多聚谷氨酰胺毒性（88）。激活ERAD反应的治疗也可能改善许多构象疾病的发病机制。在过去十年中，对普遍定期审议机制和生理意义的理解取得了巨大进展。蛋白质折叠和分泌、转录和翻译激活以及蛋白质降解过程密切相关，以维持内质网的内稳态。各种环境损害、遗传性疾病和UPR功能的潜在遗传修饰因子有助于不同疾病状态的发病机制。随着我们对控制UPR激活的机制有了更深入的了解，应该有可能发现激活或抑制UPR的方法，以获得所需的治疗效果。
A variety of approaches have been employed to identify the UPR signaling components, their function, and their physiological role. Yeast genetics allowed the definition of the basic ER stress–signaling pathway. The identification of homologous and parallel signaling pathways in higher eukaryotes has produced a mechanistic framework the cell uses to sense and compensate for ER over-load and stress. The high-level tissue-specific expression patterns of several ER stress–signaling molecules indicated the pancreas and intestine as organs that require UPR for physiological function. Analysis of UPR-induced gene expression established that protein degradation is required to reduce the stress of unfolded protein accumulation in the ER. Major advances in identifying UPR function and relevance to disease were derived from mutation of UPR signaling components in model organisms and the identification of mutations in humans. Despite tremendous progress, our knowledge of the UPR pathway remains incomplete. Further studies promise to expand our understanding of how ER stress impacts the other cellular signaling pathways. It will be very exciting and informative to understand how the UPR varies when critical components are genetically manipulated by deletion or other types of mutations. In addition, although the accumulation of unfolded protein in the ER is now known to contribute to pathogenesis in a variety of diseases, there are still few therapeutic approaches that target these events. With a greater understanding of protein-folding processes, pharmacological intervention with chemical chaperones to promote proper folding becomes feasible, as observed with sodium phenylbutyrate for Δ508 CFTR (see Gelman and Kopito, this Perspective series, ref. 53). Future intervention should consider activation of different subpathways of the UPR or overexpression of appropriate protein chaperones, as in the case of overexpression of the J domain of cytosolic HSP70, which suppresses polyglutamine toxicity in flies (88). Treatments that activate the ERAD response may also ameliorate pathogenesis in a number of the conformational diseases. Over the past ten years, tremendous progress has been made in understanding the mechanisms and physiological significance of the UPR. The processes of protein folding and secretion, transcriptional and translational activation, and protein degradation are intimately interconnected to maintain homeostasis in the ER. A variety of environmental insults, genetic disease, and underlying genetic modifiers of UPR function contribute to the pathogenesis of different disease states. As we gain a greater understanding of the mechanisms that control UPR activation, it should be possible to discover methods to activate or inhibit the UPR as desired for therapeutic benefit.