Heat Shock Response Modulators as Therapeutic Tools for Diseases of Protein Conformation

Sandy D Westerheide,Richard I Morimoto

doi:10.1074/jbc.r500010200

Sandy D Westerheide, Richard I Morimoto

Open Access

https://doi.org/10.1074/jbc.r500010200

Copy DOI

Abstract

The disruption of protein folding quality control results in the accumulation of a non-native protein species that can form oligomers, aggregates, and inclusions indicative of neurodegenerative disease. Likewise for over 100 other human diseases of protein confirmation, a common feature may be the formation of off-pathway folding intermediates that are unstable, self-associate, and with time lead to a chronic imbalance in protein homeostasis with deleterious consequences on cellular function. This has led to a hypothesis that enhancement of components of the cellular quality control machinery, specifically the levels and activities of molecular chaperones, suppress aggregation and toxicity phenotypes to allow cellular function to be restored. This review addresses the regulation of molecular chaperones and components of protein homeostasis by heat shock transcription factor 1 (HSF1), the master stress-inducible regulator, and our current understanding of pharmacologically active small molecule regulators of the heat shock response as a therapeutic strategy for protein conformational diseases.

Highlights

The heat shock response (HSR)2 is an ordered genetic response to diverse environmental and physiological stressors that results in the immediate induction of genes encoding molecular chaperones, proteases, and other proteins essential for protection and recovery from cellular damage associated with the expression of misfolded proteins (Fig. 1)
The heat shock gene superfamily is organized by molecular size and functional class, including the Hsp100, Hsp90, Hsp70, Hsp60, Hsp40 (J-domain proteins), and small heat shock protein families
The heat shock response has recently been implicated in the regulation of longevity in Caenorhabditis elegans in a pathway that overlaps with the insulin signaling pathway [13, 14]

Summary

Introduction

The heat shock response (HSR)2 is an ordered genetic response to diverse environmental and physiological stressors that results in the immediate induction of genes encoding molecular chaperones, proteases, and other proteins essential for protection and recovery from cellular damage associated with the expression of misfolded proteins (Fig. 1). The HSR and heat shock proteins have been implicated in many of these neurodegenerative diseases based on the association of chaperones with intracellular aggregates. MINIREVIEW: Heat Shock Response and Disease genes encoding Hsp70, Hsp90, and sHsps are transcribed constitutively due to multiple basal factors or binding of low levels of HSF1.

Results

Conclusion