期刊
ACS CHEMICAL BIOLOGY
卷 9, 期 6, 页码 1273-1283出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb500062n
关键词
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资金
- NHLBI [HL099245]
- Uehara Memorial Foundation
- American Cancer Society
- Ellison Medical Foundation
- National Institutes of Health [AG036634, AG046495, GM038109, GM081192, AG026647, NS047331]
- Daniel F. and Ada L. Rice Foundation
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 proteostatsis through the selective targeting of HSF1.
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