Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, USA.
J Hepatol. 2011 Apr;54(4):795-809. doi: 10.1016/j.jhep.2010.11.005. Epub 2010 Nov 13.
The unfolded protein response (UPR) is activated upon the accumulation of misfolded proteins in the endoplasmic reticulum (ER) that are sensed by the binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78). The accumulation of unfolded proteins sequesters BiP so it dissociates from three ER-transmembrane transducers leading to their activation. These transducers are inositol requiring (IRE) 1α, PKR-like ER kinase (PERK), and activating transcription factor (ATF) 6α. PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) resulting in global mRNA translation attenuation, and concurrently selectively increases the translation of several mRNAs, including the transcription factor ATF4, and its downstream target CHOP. IRE1α has kinase and endoribonuclease (RNase) activities. IRE1α autophosphorylation activates the RNase activity to splice XBP1 mRNA, to produce the active transcription factor sXBP1. IRE1α activation also recruits and activates the stress kinase JNK. ATF6α transits to the Golgi compartment where it is cleaved by intramembrane proteolysis to generate a soluble active transcription factor. These UPR pathways act in concert to increase ER content, expand the ER protein folding capacity, degrade misfolded proteins, and reduce the load of new proteins entering the ER. All of these are geared toward adaptation to resolve the protein folding defect. Faced with persistent ER stress, adaptation starts to fail and apoptosis occurs, possibly mediated through calcium perturbations, reactive oxygen species, and the proapoptotic transcription factor CHOP. The UPR is activated in several liver diseases; including obesity associated fatty liver disease, viral hepatitis, and alcohol-induced liver injury, all of which are associated with steatosis, raising the possibility that ER stress-dependent alteration in lipid homeostasis is the mechanism that underlies the steatosis. Hepatocyte apoptosis is a pathogenic event in several liver diseases, and may be linked to unresolved ER stress. If this is true, restoration of ER homeostasis prior to ER stress-induced cell death may provide a therapeutic rationale in these diseases. Herein we discuss each branch of the UPR and how they may impact hepatocyte function in different pathologic states.
未折叠蛋白反应 (UPR) 是在内质网 (ER) 中错误折叠蛋白积累时被结合免疫球蛋白蛋白 (BiP)/葡萄糖调节蛋白 78 (GRP78) 感知而激活的。未折叠蛋白的积累会使 BiP 隔离，从而使其与三种 ER 跨膜转导物分离，导致它们被激活。这些转导物是肌醇需求 (IRE) 1α、PKR 样内质网激酶 (PERK) 和激活转录因子 (ATF) 6α。PERK 磷酸化真核起始因子 2α (eIF2α)，导致全局 mRNA 翻译衰减，同时选择性地增加几种 mRNA 的翻译，包括转录因子 ATF4 及其下游靶标 CHOP。IRE1α 具有激酶和内切核酸酶 (RNase) 活性。IRE1α 的自身磷酸化激活 RNase 活性，使 XBP1 mRNA 剪接，产生活性转录因子 sXBP1。IRE1α 的激活还招募并激活应激激酶 JNK。ATF6α 转运到高尔基体区室，在那里通过跨膜蛋白水解切割产生可溶性活性转录因子。这些 UPR 途径协同作用，增加 ER 含量，扩大 ER 蛋白折叠能力，降解错误折叠的蛋白质，并减少进入 ER 的新蛋白质的负荷。所有这些都是为了适应解决蛋白质折叠缺陷。面对持续的 ER 应激，适应开始失败，细胞凋亡发生，可能通过钙波动、活性氧和促凋亡转录因子 CHOP 介导。UPR 在几种肝脏疾病中被激活；包括肥胖相关的脂肪性肝病、病毒性肝炎和酒精性肝损伤，所有这些都与脂肪变性有关，这增加了 ER 应激依赖性脂质稳态改变是脂肪变性的潜在机制的可能性。肝细胞凋亡是几种肝脏疾病的一种致病事件，可能与未解决的 ER 应激有关。如果这是真的，在 ER 应激诱导的细胞死亡之前恢复 ER 稳态可能为这些疾病提供治疗依据。本文讨论了 UPR 的每个分支，以及它们在不同病理状态下如何影响肝细胞功能。
