Department of Molecular & Experimental Medicine, Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
ACS Chem Biol. 2014 Jun 20;9(6):1273-83. doi: 10.1021/cb500062n. Epub 2014 Apr 16.
The heat shock response is an evolutionarily conserved, stress-responsive signaling pathway that adapts cellular proteostasis in response to pathologic insult. In metazoans, the heat shock response primarily functions through the posttranslational activation of heat shock factor 1 (HSF1), a stress-responsive transcription factor that induces the expression of cytosolic proteostasis factors including chaperones, cochaperones, and folding enzymes. HSF1 is a potentially attractive therapeutic target to ameliorate pathologic imbalances in cellular proteostasis associated with human disease, although the underlying impact of stress-independent HSF1 activation on cellular proteome composition remains to be defined. Here, we employ a highly controllable, ligand-regulated HSF1 that activates HSF1 to levels compatible with those that could be achieved using selective small molecule HSF1 activators. Using a combination of RNAseq and quantitative proteomics, we define the impact of stress-independent HSF1 activation on the composition of the cellular proteome. We show that stress-independent HSF1 activation selectively remodels cytosolic proteostasis pathways without globally influencing the composition of the cellular proteome. Furthermore, we show that stress-independent HSF1 activation decreases intracellular aggregation of a model polyglutamine-containing protein and reduces the cellular toxicity of environmental toxins like arsenite that disrupt cytosolic proteostasis. Collectively, our results reveal a proteome-level view of stress-independent HSF1 activation, providing a framework to establish therapeutic approaches to correct pathologic imbalances in cellular proteostasis through the selective targeting of HSF1.
热休克反应是一种进化上保守的应激反应信号通路，可适应细胞内的蛋白质稳态，以应对病理损伤。在真核生物中，热休克反应主要通过热休克因子 1（HSF1）的翻译后激活来发挥作用，HSF1 是一种应激反应转录因子，可诱导包括伴侣蛋白、共伴侣蛋白和折叠酶在内的细胞质蛋白质稳态因子的表达。HSF1 是一种有吸引力的治疗靶点，可以改善与人类疾病相关的细胞蛋白质稳态的病理失衡，尽管应激非依赖性 HSF1 激活对细胞蛋白质组组成的潜在影响仍有待确定。在这里，我们采用了一种高度可控的、配体调控的 HSF1，它可以激活 HSF1 到与使用选择性小分子 HSF1 激活剂所能达到的水平相兼容的水平。我们使用 RNAseq 和定量蛋白质组学相结合的方法，定义了应激非依赖性 HSF1 激活对细胞蛋白质组组成的影响。我们表明，应激非依赖性 HSF1 激活选择性地重塑了细胞质蛋白质稳态途径，而不会全局影响细胞蛋白质组的组成。此外，我们还表明，应激非依赖性 HSF1 激活可减少模型多聚谷氨酰胺蛋白的细胞内聚集，并降低环境毒素（如破坏细胞质蛋白质稳态的亚砷酸盐）的细胞毒性。总的来说，我们的结果揭示了应激非依赖性 HSF1 激活的蛋白质组水平视图，为通过选择性靶向 HSF1 来纠正细胞蛋白质稳态的病理失衡提供了一个治疗方法的框架。
