Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, T228, Mailstop BCM-315, Houston, TX 77030-3498, USA.
Proc Am Thorac Soc. 2010 Nov;7(6):376-80. doi: 10.1513/pats.201001-011AW.
α(1)-Antitrypsin (AAT) secreted from hepatocytes is an inhibitor of neutrophil elastase. Its normal circulating concentration functions to maintain the elasticity of the lung by preventing the hydrolytic destruction of elastin fibers. Severely diminished circulating concentrations of AAT, resulting from the impaired secretion of genetic variants that exhibit distinct polypeptide folding defects, can function as an etiologic agent for the development of chronic obstructive pulmonary disease. In addition, the inappropriate accumulation of structurally aberrant AAT within the hepatocyte endoplasmic reticulum can contribute to the etiology of liver disease. This article focuses on the discovery and characterization of a biosynthetic quality control system that contributes to the secretion of AAT by first facilitating its proper structural maturation, and then by orchestrating the selective elimination of those molecules that fail to attain structural maturation. Mechanistic elucidation of these interconnected quality control events recently led to the identification of an underlying genetic modifier capable of accelerating the onset of end-stage liver disease by impairing the efficiency of an initial step in the protein disposal process.
α(1)-抗胰蛋白酶（AAT）由肝细胞分泌，是中性粒细胞弹性蛋白酶的抑制剂。其正常循环浓度通过防止弹性纤维的水解破坏，来维持肺的弹性。由于遗传变异体的分泌受损，导致 AAT 的循环浓度严重降低，这些遗传变异体表现出明显的多肽折叠缺陷，可作为慢性阻塞性肺疾病发展的病因。此外，结构异常的 AAT 在肝细胞内质网中的不当积累也可能导致肝病的发生。本文重点介绍了生物合成质量控制系统的发现和特征，该系统通过首先促进其适当的结构成熟，然后协调选择性消除那些未能达到结构成熟的分子，从而促进 AAT 的分泌。最近，对这些相互关联的质量控制事件的机制阐明导致鉴定出一种潜在的遗传修饰因子，该因子能够通过削弱蛋白处置过程初始步骤的效率来加速终末期肝病的发生。
