测量组蛋白去乙酰化酶抑制剂（HDACi）对α-1抗胰蛋白酶分泌及活性的影响。
Measuring the Effect of Histone Deacetylase Inhibitors (HDACi) on the Secretion and Activity of Alpha-1 Antitrypsin.
作者信息
Wang Chao, Bouchecareilh Marion, Balch William E
机构信息
Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, Bordeaux, France.
出版信息
Methods Mol Biol. 2017;1639:185-193. doi: 10.1007/978-1-4939-7163-3_18.
Alpha-1 antitrypsin deficiency (AATD) is a protein conformational disease with the most common cause being the Z-variant mutation in alpha-1 antitrypsin (Z-AAT). The misfolded conformation triggered by the Z-variant disrupts cellular proteostasis (protein folding) systems and fails to meet the endoplasmic reticulum (ER) export metrics, leading to decreased circulating AAT and deficient antiprotease activity in the plasma and lung. Here, we describe the methods for measuring the secretion and neutrophil elastase (NE) inhibition activity of AAT/Z-AAT, as well as the response to histone deacetylase inhibitor (HDACi), a major proteostasis modifier that impacts the secretion and function of AATD from the liver to plasma. These methods provide a platform for further therapeutic development of proteostasis regulators for AATD.
α-1抗胰蛋白酶缺乏症（AATD）是一种蛋白质构象疾病，最常见的病因是α-1抗胰蛋白酶（Z-AAT）中的Z变体突变。Z变体引发的错误折叠构象破坏了细胞蛋白质稳态（蛋白质折叠）系统，无法满足内质网（ER）的输出标准，导致循环中的AAT减少，血浆和肺中的抗蛋白酶活性不足。在此，我们描述了测量AAT/Z-AAT的分泌和中性粒细胞弹性蛋白酶（NE）抑制活性的方法，以及对组蛋白去乙酰化酶抑制剂（HDACi）的反应，HDACi是一种主要的蛋白质稳态调节剂，会影响AATD从肝脏到血浆的分泌和功能。这些方法为AATD蛋白质稳态调节剂的进一步治疗开发提供了一个平台。
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