Endoplasmic reticulum stress - A double edged sword for Z alpha-1 antitrypsin deficiency hepatoxicity
Endoplasmic reticulum stress - A double edged sword for Z alpha-1 antitrypsin deficiency hepatoxicity
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DOI：
10.1016/j.biocel.2008.02.008
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发表时间：
2008-01-01
影响因子：
4
通讯作者：
Norfis, Suzanne
中科院分区：
文献类型：
--
作者：
Lawless, Matthew W.;Mankan, Arun K.;Norfis, Suzanne
几种不同的疾病，包括肝脏疾病Z α-1抗胰蛋白酶缺乏症以及囊性纤维化、阿尔茨海默病和帕金森病，都是由相同的一般疾病机制引起的，现在被归类为术语“构象疾病”，其特征在于潜在蛋白质的异常折叠和随后的聚集。近年来，一些重要的研究进展，在细胞生物学的聚集倾向的突变蛋白和肝脏疾病的病理生物学机制一般已被证明是至关重要的，我们的理解Z α-1抗胰蛋白酶缺乏症。这种肝脏疾病强调了内质网应激的四大支柱中包含的构象障碍的主要机制：（1）蛋白质降解，（2）内质过载反应，（3）未折叠蛋白质反应和（4）细胞死亡途径。Z α-1抗胰蛋白酶肝毒性的四阶段模型简单而优雅，有助于解释这种疾病的临床表现。内质网应激反应已经进化为保护性的，然而当它们无效时，就会发生毒性损伤，这表明这些反应可以被描述为一把双刃剑。在这种背景下，现代生物学中最令人困惑的问题之一是了解细胞如何在适应和死亡之间做出“选择”以应对压力。当一种途径成为主导时，一种微妙的平衡就会被打破，适应性或致命性反应就会出现。了解内质网应激信号如何在指导临床结果中发挥作用，可能会导致更好的前景，更合理的方法来研究和治疗这种肝脏疾病。(C)2008爱思唯尔有限公司保留所有权利。
Several diverse disorders, including the liver disorder Z alpha-1 antitrypsin deficiency as well as cystic fibrosis, Alzheimer's, and Parkinson's disease arise from the same general disease mechanism and are now categorized under the term "conformational diseases", characterized by abnormal folding and subsequent aggregation of an underlying protein. In recent years, several important research advances in the cell biology of aggregation-prone mutant proteins and pathobiological mechanisms of liver disease in general have proven paramount to our understanding of Z alpha-1 antitrypsin deficiency. This liver disease underlines the principle mechanisms of conformational disorders contained within the four pillars of endoplasmic reticulum stress: (1) protein degradation, (2) endoplasmic overload response, (3) unfolded protein response and (4) cellular death pathway. This four-stage model of Z alpha-1 antitrypsin hepatoxicity is elegant in its simplicity and helps explain the clinical manifestations of this condition. Endoplasmic reticulum stress responses have evolved to be protective, however when they are ineffective, toxic damage occurs demonstrating how these responses can be described as a double edged sword. In this context, one of the most perplexing problems in modem biology is to understand how the cell "chooses" between adaptation and demise in response to stress. When one pathway becomes predominant, a delicate balance is perturbed and either an adaptive or a lethal response ensues. Understanding how the endoplasmic reticulum stress signals potentially play a role in directing a clinical outcome may lead to better prospects of more rational approaches to investigation and therapy for this liver disease. (C) 2008 Elsevier Ltd. All rights reserved.