Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
EMBO J. 2013 May 15;32(10):1451-68. doi: 10.1038/emboj.2013.87. Epub 2013 Apr 19.
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 Aβ-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.
蛋白质合成对环境和生理挑战的适应对于细胞活力至关重要。在这里，我们通过核糖体结合伴侣蛋白 NAC（新生多肽相关复合物）的功能特性表明，翻译与细胞的蛋白质折叠环境紧密相关。在非胁迫条件下，NAC 与核糖体结合以促进翻译和蛋白质折叠。当蛋白质稳态失衡时，NAC 从核糖体相关状态重新定位到蛋白质聚集体，发挥伴侣蛋白的作用。这导致 NAC 从核糖体上的功能耗竭，从而降低翻译能力和新生蛋白质的通量。在衰老过程中、热休克以及高度聚集倾向的多聚谷氨酰胺扩展蛋白和 Aβ 肽表达时，我们观察到 NAC 从多核糖体中耗竭并重新定位于蛋白质聚集体。这些结果表明，NAC 作为一种蛋白质稳态传感器具有核心作用，为细胞提供了一种调节反馈机制，其中翻译活性也受到细胞蛋白质组折叠状态和细胞对压力的反应的控制。
