Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of α1-Antitrypsin Deficiency
Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of α1-Antitrypsin Deficiency
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DOI：
10.1074/jbc.m112.404707
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发表时间：
2012-11-02
影响因子：
4.8
通讯作者：
Balch, William E.
中科院分区：
文献类型：
--
作者：
Bouchecareilh, Marion;Hutt, Darren M.;Balch, William E.
α 1-抗胰蛋白酶（α 1AT）缺乏症（α 1ATD）是α 1AT响应于其与内质网蛋白质稳定机制相互作用的缺陷而折叠、运输和分泌缺陷的结果。最常见和最严重的α 1ATD形式由Z变体引起，其特征在于α 1AT聚合物在肝脏内质网中蓄积，导致血清中α 1AT及其在肺中的抗蛋白酶活性严重降低（>85%）。在这个器官中，α 1AT通过抑制中性粒细胞弹性蛋白酶（一种降解弹性蛋白的蛋白酶）来确保组织完整性。鉴于α 1ATD的治疗选择有限，需要更详细地了解控制α 1AT生物发生的折叠和运输生物学及其对小分子调节剂的反应。在此，我们报告了组蛋白去乙酰化酶（HDAC）抑制剂辛二酰苯胺异羟肟酸（SAHA）治疗后Z-α 1 AT分泌的校正，部分通过HDAC 7沉默起作用，并涉及钙连接蛋白敏感机制。SAHA介导的校正使Z-α 1AT分泌和丝氨酸蛋白酶抑制剂活性恢复到野生型α 1AT所观察到的水平的50%。这些数据表明，HDAC活性可以影响Z-α 1AT蛋白运输，SAHA可能代表α 1ATD和其他蛋白质错误折叠疾病的潜在治疗方法。
alpha 1-Antitrypsin (alpha 1AT) deficiency (alpha 1ATD) is a consequence of defective folding, trafficking, and secretion of alpha 1AT in response to a defect in its interaction with the endoplasmic reticulum proteostasis machineries. The most common and severe form of alpha 1ATD is caused by the Z-variant and is characterized by the accumulation of alpha 1AT polymers in the endoplasmic reticulum of the liver leading to a severe reduction (>85%) of alpha 1AT in the serum and its anti-protease activity in the lung. In this organ alpha 1AT is critical for ensuring tissue integrity by inhibiting neutrophil elastase, a protease that degrades elastin. Given the limited therapeutic options in alpha 1ATD, a more detailed understanding of the folding and trafficking biology governing alpha 1AT biogenesis and its response to small molecule regulators is required. Herein we report the correction of Z-alpha 1AT secretion in response to treatment with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), acting in part through HDAC7 silencing and involving a calnexin-sensitive mechanism. SAHA-mediated correction restores Z-alpha 1AT secretion and serpin activity to a level 50% that observed for wild-type alpha 1AT. These data suggest that HDAC activity can influence Z-alpha 1AT protein traffic and that SAHA may represent a potential therapeutic approach for alpha 1ATD and other protein misfolding diseases.