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Characterizing the altered cellular proteome induced by the stress-independent activation of heat shock factor 1

Academic Article
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Overview

related to degree

  • Ryno, Lisa, Ph.D. in Chemistry, Scripps Research 2008 - 2012

authors

  • Ryno, Lisa
  • Genereux, J. C.
  • Naito, T.
  • Morimoto, R. I.
  • Powers, Evan
  • Shoulders, M. D.
  • Wiseman, R. Luke

publication date

  • 2014

journal

  • ACS Chemical Biology  Journal

abstract

  • 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.

subject areas

  • Biomarkers
  • Blotting, Western
  • Chromatography, Liquid
  • DNA-Binding Proteins
  • Gene Regulatory Networks
  • Genome, Human
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Proteome
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stress, Physiological
  • Tandem Mass Spectrometry
  • Transcription Factors
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Identity

PubMed Central ID

  • PMC4076015

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb500062n

PubMed ID

  • 24689980
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Additional Document Info

start page

  • 1273

end page

  • 1283

volume

  • 9

issue

  • 6

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