The proteostasis boundary in misfolding diseases of membrane traffic.
The proteostasis boundary in misfolding diseases of membrane traffic.
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DOI：
10.1016/j.febslet.2009.07.014
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发表时间：
2009-08-20
期刊：
影响因子：
3.5
通讯作者：
Balch, William E.
中科院分区：
文献类型：
--
作者：
Hutt, Darren M.;Powers, Evan T.;Balch, William E.
蛋白质功能受蛋白质静止网络（PN）的调节（Balch et al. (2008) Science, 319:916）， PN是一个生成和保护蛋白质折叠的综合生物系统。PN的组成受未折叠蛋白反应（UPR）、热休克反应（HSR）、泛素蛋白酶体系统（UPS）和表观遗传程序等信号通路的调控。真核细胞通过胞外和内吞途径的膜运输过程中蛋白质折叠和功能管理不当是导致多种疾病的原因，其中包括溶酶体贮积病、髓鞘疾病、囊性纤维化、系统性淀粉样病变（如轻链骨髓瘤）和包括阿尔茨海默氏症在内的神经退行性疾病。错误折叠的毒性可以是细胞自主（影响产生细胞）或细胞非自主（影响非产生细胞）或两者兼而有之，并且具有功能丧失或毒性功能获得表型。在此，我们回顾了PN及其调控转录回路在膜运输过程中可能在管理蛋白质折叠和功能方面的作用。我们强调“proteostasis boundary （PB）”的启用原则（Evans等人，2009）。学生物化学启。在出版社，Epub)。折叠动力学和热力学以及错误折叠动力学的综合效应决定了不同类型细胞的可变和可调PN容量。PN的差异解释了蛋白质折叠和健康功能的多功能性，以及疾病中细胞和组织对突变和环境挑战的反应。我们讨论了如何通过代谢物和药物干预来操纵折叠能量学或PB，为影响人类健康的贩运疾病的生物功能恢复提供了多种途径。
Protein function is regulated by the proteostasis network (PN) (Balch et al. (2008) Science, 319:916), an integrated biological system that generates and protects the protein fold. The composition of the PN is regulated by signaling pathways including the unfolded protein response (UPR), the heat shock response (HSR), the ubiquitin proteasome system (UPS) and epigenetic programs. Mismanagement of protein folding and function during membrane trafficking through the exocytic and endocytic pathways of eukaryotic cells by the PN is responsible for a wide range of diseases that include, among others, lysosomal storage diseases, myelination diseases, cystic fibrosis, systemic amyloidoses such as light chain myeloma, and neurodegenerative diseases including Alzheimer’s. Toxicity from misfolding can be cell autonomous (affect the producing cell) or cell non-autonomous (affect a non-producing cell) or both, and have either a loss-of-function or gain-of-toxic function phenotype. Herein, we review the role of the PN and its regulatory transcriptional circuitry likely to be operational in managing the protein fold and function during membrane trafficking. We emphasize the enabling principle of a ‘proteostasis boundary (PB)’ (Evans et al. (2009) Ann. Rev. Biochem. In press, Epub). The PB is defined by the combined effects of the kinetics and thermodynamics of folding and the kinetics of misfolding, which are linked to the variable and adjustable PN capacity found different cell types. Differences in the PN account for the versatility of protein folding and function in health, and the cellular and tissue response to mutation and environmental challenges in disease. We discuss how manipulation of the folding energetics or the PB through metabolites and pharmacological intervention provides multiple routes for restoration of biological function in trafficking disease affecting human health.
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