Activation of Endoplasmic Reticulum-Specific Stress Responses Associated with the Conformational Disease Z α1-Antitrypsin Deficiency1
Activation of Endoplasmic Reticulum-Specific Stress Responses Associated with the Conformational Disease Z α1-Antitrypsin Deficiency1
复制标题
与构象疾病 Z α1-抗胰蛋白酶缺乏相关的内质网特异性应激反应的激活1
作者：
M. Lawless;C. Greene;A. Mulgrew;C. Taggart;S. O’Neill;N. McElvaney
构象性疾病是一类与组织和细胞区室中异常蛋白质积累相关的疾病。Z α1-抗胰蛋白酶（A1 AT）缺乏症是一种与错误折叠的A1 AT在肝细胞内质网（ER）中积聚相关的遗传性疾病。我们试图使用ZA 1AT ER积累的体外模型系统来鉴定ZA 1AT诱导的肝病的分子发病机制中涉及的细胞内事件。我们研究了Z A1 AT诱导的ER应激信号，并证明了ER过载反应和未折叠蛋白反应都被突变型Z A1 AT激活，但不是野生型M A1 AT。有趣的是，未折叠蛋白反应途径的激活需要额外的损伤，而NF-κB激活，ER过载反应的标志，是组成性的。这些发现对Z A1 AT肝病未来治疗方法的设计具有重要意义，也可能影响其他构象疾病的药物设计。
Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z α1-antitrypsin (A1AT) deficiency is a genetic disease associated with accumulation of misfolded A1AT in the endoplasmic reticulum (ER) of hepatocytes. We sought to identify intracellular events involved in the molecular pathogenesis of Z A1AT-induced liver disease using an in vitro model system of Z A1AT ER accumulation. We investigated ER stress signals induced by Z A1AT and demonstrated that both the ER overload response and the unfolded protein response were activated by mutant Z A1AT, but not wild-type M A1AT. Interestingly, activation of the unfolded protein response pathway required an additional insult, whereas NF-κB activation, a hallmark of the ER overload response, was constitutive. These findings have important implications for the design of future therapeutics for Z A1AT liver disease and may also impact on drug design for other conformational diseases.
人 PiZ α1-抗胰蛋白酶变体的可溶性聚集体在内质网内通过对蛋白质合成抑制剂敏感的机制被降解。
DOI：
--
发表时间：
1992
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Le,A;Ferrell,GA;Dishon,DS;Le,QQ;Sifers,RN
通讯作者：
Sifers,RN
影响因子：
--
作者：
A. Welihinda;W. Tirasophon;R. Kaufman
通讯作者：
A. Welihinda;W. Tirasophon;R. Kaufman
DOI：
10.1073/pnas.97.4.1796
发表时间：
2000-02-15
影响因子：
11.1
作者：
Burrows, JAJ;Willis, LK;Perlmutter, DH
通讯作者：
Perlmutter, DH