The Stress of Protein Misfolding: From Single Cells to Multicellular Organisms
The Stress of Protein Misfolding: From Single Cells to Multicellular Organisms
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DOI：
10.1101/cshperspect.a009704
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发表时间：
2011-06-01
影响因子：
7.2
通讯作者：
Morimoto, Richard I.
中科院分区：
文献类型：
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作者：
Gidalevitz, Tali;Prahlad, Veena;Morimoto, Richard I.
生物体通过改变其新陈代谢、生长和繁殖的速率来适应环境的变化。同时，系统必须确保其大分子的稳定性和功能性。环境中的波动是由高度保守的应激反应和稳态机制感知的，其中，热休克反应（HSR）代表了对急性和慢性蛋白毒性损伤的基本反应。然而，与维持基因组完整性的策略不同，蛋白质组的保护必须适应非天然蛋白质的正常流动以及细胞之间和个体之间蛋白质组成的差异。此外，成体细胞可能在合成和清除率方面存在显著差异，这些差异受到蛋白质表达、遗传多态性以及生理和环境条件波动的内在错误的影响。在这里，我们将讨论如何在细胞和生物体水平上实现蛋白质稳态（蛋白质稳态），以及如何设置应激反应的阈值以检测和对抗蛋白质错误折叠。对于后生动物，协调功能和生长的要求对错误折叠的检测、信号传导和响应施加了额外的约束，并要求HSR整合到生物体生理学的各个方面，如寿命。这是通过细胞代谢状态对热休克因子1（HSF 1）的分级调节和集中的神经元控制来实现的，神经元控制可以实现细胞和组织之间的最佳资源分配。我们将研究单个细胞中的蛋白质折叠质量控制机制如何整合到多细胞水平的控制中，甚至是定制设计以支持个体变异性并对进化适应施加额外的限制。
Organisms survive changes in the environment by altering their rates of metabolism, growth, and reproduction. At the same time, the system must ensure the stability and functionality of its macromolecules. Fluctuations in the environment are sensed by highly conserved stress responses and homeostatic mechanisms, and of these, the heat shock response (HSR) represents an essential response to acute and chronic proteotoxic damage. However, unlike the strategies employed to maintain the integrity of the genome, protection of the proteome must be tailored to accommodate the normal flux of nonnative proteins and the differences in protein composition between cells, and among individuals. Moreover, adult cells are likely to have significant differences in the rates of synthesis and clearance that are influenced by intrinsic errors in protein expression, genetic polymorphisms, and fluctuations in physiological and environmental conditions. Here, we will address how protein homeostasis (proteostasis) is achieved at the level of the cell and organism, and how the threshold of the stress response is set to detect and combat protein misfolding. For metazoans, the requirement for coordinated function and growth imposes additional constraints on the detection, signaling, and response to misfolding, and requires that the HSR is integrated into various aspects of organismal physiology, such as lifespan. This is achieved by hierarchical regulation of heat shock factor 1 (HSF1) by the metabolic state of the cell and centralized neuronal control that could allow optimal resource allocation between cells and tissues. We will examine how protein folding quality control mechanisms in individual cells may be integrated into a multicellular level of control, and further, even custom-designed to support individual variability and impose additional constraints on evolutionary adaptation.