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

Lisa M. Ryno, Joseph C. Genereux, Tadasuke Naito, Richard I. Morimoto, Evan T. Powers, Matthew D. Shoulders, R. Luke Wiseman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1273-1283
Number of pages11
JournalACS chemical biology
Volume9
Issue number6
DOIs
StatePublished - Jun 20 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Fingerprint Dive into the research topics of 'Characterizing the altered cellular proteome induced by the stress-independent activation of heat shock factor 1'. Together they form a unique fingerprint.

Cite this