Proteostasis strategies for restoring alpha1-antitrypsin deficiency.
Proteostasis strategies for restoring alpha1-antitrypsin deficiency.
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DOI：
10.1513/pats.201001-016aw
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发表时间：
2010-11-01
期刊：
影响因子：
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通讯作者：
Balch, William E
中科院分区：
文献类型：
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作者：
Bouchecareilh, Marion;Conkright, Juliana J;Balch, William E
人类蛋白质组的功能由蛋白质稳态网络（PN）（Science 2008;319：916; Science 2010;329：766）定义，蛋白质稳态网络是一种生物系统，其产生、保护和在必要时降解蛋白质以优化细胞、组织和生物体对饮食、应激和衰老的响应。许多人类疾病是由于蛋白质不能正确折叠以响应突变，从而破坏了蛋白质组。在胞吐途径的情况下，这包括指导折叠和从内质网（ER）输出蛋白质的蛋白质稳定组分。这里包括丝氨酸蛋白酶抑制剂缺乏症，这是一类导致丝氨酸蛋白酶抑制剂从肝脏分泌到血清中的显著减少的相关疾病。作为对错误折叠的响应，丝氨酸蛋白酶α（1）-抗胰蛋白酶（α 1AT）的变体不能离开ER，并被靶向ER相关降解或自噬途径。开发alpha 1AT缺陷疗法的挑战是了解参与折叠和输出的PN途径。在此，我们回顾了PN在ER合成和运输到细胞表面或细胞外空间过程中管理蛋白质折叠和功能的作用。我们强调了蛋白质稳态边界的作用，以定义蛋白质组的操作（Annu Rev Biochem 2009;78：959）。我们讨论了如何通过药理学干预来操纵折叠能量学或PN，从而为恢复变体alpha 1AT功能提供多种途径，以造福人类健康。
The function of the human proteome is defined by the proteostasis network (PN) (Science 2008;319:916; Science 2010;329:766), a biological system that generates, protects, and, where necessary, degrades a protein to optimize the cell, tissue, and organismal response to diet, stress, and aging. Numerous human diseases result from the failure of proteins to fold properly in response to mutation, disrupting the proteome. In the case of the exocytic pathway, this includes proteostasis components that direct folding, and export of proteins from the endoplasmic reticulum (ER). Included here are serpin deficiencies, a class of related diseases that result in a significant reduction of secretion of serine proteinase inhibitors from the liver into serum. In response to misfolding, variants of the serine protease alpha(1)-antitrypsin (alpha1AT) fail to exit the ER and are targeted for either ER-associated degradation or autophagic pathways. The challenge for developing alpha1AT deficiency therapeutics is to understand the PN pathways involved in folding and export. Herein, we review the role of the PN in managing the protein fold and function during synthesis in the ER and trafficking to the cell surface or extracellular space. We highlight the role of the proteostasis boundary to define the operation of the proteome (Annu Rev Biochem 2009;78:959). We discuss how manipulation of folding energetics or the PN by pharmacological intervention could provide multiple routes for restoration of variant alpha1AT function to the benefit of human health.