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Review
. 2012 Oct 15;25(10):2036-53.
doi: 10.1021/tx300264x. Epub 2012 Jul 31.

Small molecule activators of the heat shock response: chemical properties, molecular targets, and therapeutic promise

James D West  1 , Yanyu Wang, Kevin A Morano
Affiliations
Review

Small molecule activators of the heat shock response: chemical properties, molecular targets, and therapeutic promise

James D West et al. Chem Res Toxicol. .

Abstract

All cells have developed various mechanisms to respond and adapt to a variety of environmental challenges, including stresses that damage cellular proteins. One such response, the heat shock response (HSR), leads to the transcriptional activation of a family of molecular chaperone proteins that promote proper folding or clearance of damaged proteins within the cytosol. In addition to its role in protection against acute insults, the HSR also regulates lifespan and protects against protein misfolding that is associated with degenerative diseases of aging. As a result, identifying pharmacological regulators of the HSR has become an active area of research in recent years. Here, we review progress made in identifying small molecule activators of the HSR, what cellular targets these compounds interact with to drive response activation, and how such molecules may ultimately be employed to delay or reverse protein misfolding events that contribute to a number of diseases.

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Figures

Figure 1
Figure 1. Parallel Stress Pathways
The antioxidant response, ER stress response, and HSR pathways help maintain cellular homeostasis following exposure to different environmental stresses.
Figure 2
Figure 2. HSF1 Domain Structure
HSF1 has three principal domains that facilitate its regulation of Hsp genes in response to stress. The DNA binding domain can bind inverted 5′-nGAA-3′ repeats upon trimerization of monomeric HSF1 through its trimerization domain. The activation domain near the C-terminus is the site of many inducible post-translational modification following exposure to various stresses.
Figure 3
Figure 3. Steps in HSF1 Activation
HSF1 activation following exposure to protein-damaging stresses often involves its dissociation from various negative regulators (including Hsp70 and Hsp90), its trimerization, and its inducible post-translational modification. Post-transalational modifications to HSF1 include sumoylation (SUMO), acetylation (Ac), and phosphorylation (P).
Figure 4
Figure 4. Families of Molecules That Activate HSF1
HSF1 activators can perturb various aspects of protein homeostasis including translation, protein folding, processing, and degradation.
Figure 5
Figure 5. Thiol-Modifications by Oxidants, Transition Metals, and Organic Electrophiles
Oxidants, metals and metalloids, and organic electrophiles carry out different modifications on reactive Cys residues in target proteins.
Figure 6
Figure 6. Classes of Organic Electrophiles That Activate HSF1
Electrophiles that activate HSF1 are grouped according to the type of addition reaction that they carry out with thiol groups. An asterisk (*) indicates where thiol groups are likely to add within these molecules. More information about the physicochemical properties of these molecules and their thiol adducts is provided in Table 1.
Figure 7
Figure 7. Direct Regulation of HSF1 Under Stress Conditions
Upon exposure to several stress conditions in vitro, HSF1 undergoes trimerization and shows increased DNA binding.
Figure 8
Figure 8. Stress-Induced Derepression of HSF1 Activity
Molecular chaperones (e.g., Hsp70 and Hsp90) that bind to and repress HSF1 activity are recruited to sites of misfolded polypetides and aggregated proteins that accumulate upon exposure to many stresses, allowing HSF1 to trimerize and bind DNA. For simplicity, only Hsp70 is shown as a negative regulator in complex with HSF1.
Figure 9
Figure 9. Direct Sensing of Thiol-Reactive Compounds by Hsp70
(A) Conservation of Cys residues in Hsp70 homologs among various eukaryotic species. C264 and C303 are sites of alkylation in the S. cerevisiae Hsp70 Ssa1. (B) Hypothetical model for activation of HSF1 by thiol-reactive molecules. Hsp70 is modified on conserved Cys residues by reactive molecules, leading to its dissociation from HSF1 and subsequent steps in HSF1 activation.
Figure 10
Figure 10. Sensing by Enzymes Involved in Post-Translational Modification of HSF1
Stresses that activate the HSR may influence the activities of multiple enzymes that facilitate HSF1 post-translational modification.
Figure 11
Figure 11. Model for Therapeutic Utility of Pharmacological HSR Regulators
The HSR is altered in aging and several disease states. As a possible way of intervening in each of these physiological states, pharmacological regulators of HSF1 activity may be used to restore the HSR to normal activity levels.
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