The nascent polypeptide-associated complex is a key regulator of proteostasis
The nascent polypeptide-associated complex is a key regulator of proteostasis
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DOI：
10.1038/emboj.2013.87
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发表时间：
2013-05-15
期刊：
影响因子：
11.4
通讯作者：
Morimoto, Richard I.
中科院分区：
文献类型：
--
作者：
Kirstein-Miles, Janine;Scior, Annika;Morimoto, Richard I.
蛋白质合成对环境和生理挑战的适应是细胞生存所必需的。在这里，我们证明了翻译通过核糖体结合的伴侣蛋白NAC(新生多肽相关复合体)的功能特性与细胞的蛋白质折叠环境紧密相连。在非应激条件下，NAC与核糖体结合，促进翻译和蛋白质折叠。当蛋白质平衡失衡时，NAC以伴侣的角色从核糖体相关状态重新定位到蛋白质聚集体。这会导致核糖体中NAC的功能性耗尽，从而降低翻译能力和新生蛋白质的流量。在老化过程中，可以观察到NAC从多聚体中耗尽，并重新定位到蛋白质聚集体，以响应热休克和高度易于聚集的聚谷氨酰胺扩展蛋白和抗体多肽的表达。这些结果表明，NAC作为蛋白质平衡感受器具有中心作用，为细胞提供了一种调节反馈机制，其中翻译活动也受到细胞蛋白质组的折叠状态和细胞对应激的反应的控制。
The adaptation of protein synthesis to environmental and physiological challenges is essential for cell viability. Here, we show that translation is tightly linked to the protein-folding environment of the cell through the functional properties of the ribosome bound chaperone NAC (nascent polypeptide-associated complex). Under non-stress conditions, NAC associates with ribosomes to promote translation and protein folding. When proteostasis is imbalanced, NAC relocalizes from a ribosome-associated state to protein aggregates in its role as a chaperone. This results in a functional depletion of NAC from the ribosome that diminishes translational capacity and the flux of nascent proteins. Depletion of NAC from polysomes and re-localisation to protein aggregates is observed during ageing, in response to heat shock and upon expression of the highly aggregation-prone polyglutamine-expansion proteins and Ab-peptide. These results demonstrate that NAC has a central role as a proteostasis sensor to provide the cell with a regulatory feedback mechanism in which translational activity is also controlled by the folding state of the cellular proteome and the cellular response to stress.