title: Characterizing the altered cellular proteome induced by the stress-independent activation of heat shock factor 1.
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.
authors.affiliation: Department of Molecular & Experimental Medicine, Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ryno
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.forename: Tadasuke
authors.initials: T
authors.lastname: Naito
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D002853:Chromatography, Liquid; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks; D015894:Genome, Human; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020543:Proteome / Q000032:analysis*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D020543:Proteome; D012333:RNA, Messenger; D014157:Transcription Factors