PI 3-kinase regulatory subunits as regulators of the unfolded protein response.
PI 3-kinase regulatory subunits as regulators of the unfolded protein response.
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DOI：
10.1016/b978-0-12-385114-7.00009-x
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发表时间：
2011
影响因子：
--
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
Winnay, Jonathon N.;Kahn, C. Ronald
内质网（ER）由一个相互连接的膜网络组成，是合成和折叠膜和分泌蛋白的主要场所。在ER腔内，分子伴侣和各种酶促进蛋白质折叠，确保多肽获得其适当的三级构象。增加蛋白质合成的生理条件或干扰蛋白质获得其天然构象的过程的刺激，在蛋白质折叠需求和ER的能力之间产生不平衡。这导致未折叠或不正确折叠的蛋白质在ER腔中的积累和ER应激状态。这种细胞反应称为未折叠蛋白反应（UPR），导致三种相关的信号转导途径激活：PKR样激酶（PERK）、肌醇需要1 α（IRE 1 α）和激活转录因子6α（ATF 6 α）。总的来说，这些信号级联的组合作用通过减弱翻译以减少蛋白质合成和通过激活最终用于增加ER蛋白折叠能力的转录程序来减少ER应激。最近，我们和Park et.等人已经表征了p85α和p85β亚基作为UPR调节剂的新功能，这是由于它们能够在诱导ER应激后促进XBP-1进入核。本章介绍了最近阐明的作用PI 3-激酶的调节亚基的调节剂的UPR，并提供了方法来衡量UPR途径的激活。
The endoplasmic reticulum (ER) consists of an interconnected, membranous network that is the major site for the synthesis and folding of integral membrane and secretory proteins. Within the ER lumen, protein folding is facilitated by molecular chaperones and a variety of enzymes that ensure that polypeptides obtain their appropriate, tertiary conformation. Physiological conditions that increase protein synthesis or stimuli that disturb the processes by which proteins obtain their native conformation, create an imbalance between the protein-folding demand and capacity of the ER. This results in the accumulation of unfolded or improperly folded proteins in the ER lumen and a state of ER stress. The cellular response, referred to as the unfolded protein response (UPR), results in activation of three linked signal transduction pathways: PKR-like kinase (PERK), inositol requiring 1 α (IRE1α) and activating transcription factor 6α (ATF6α). Collectively, the combined actions of these signaling cascades serve to reduce ER stress through attenuation of translation to reduce protein synthesis and through activation of transcriptional programs that ultimately serve to increase ER protein folding capacity. Recently, we and Park et. al have characterized a novel function for the p85α and p85β subunits as modulators of the UPR by virtue of their ability to facilitate the nuclear entry of XBP-1s following induction of ER stress. This chapter describes the recently elucidated role for the regulatory subunits of PI 3-kinase as modulators of the UPR and provides methods to measure UPR pathway activation.