Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1

Details

• Alternative Title:
  ACS Chem Biol
• Personal Author:
  Moore, Christopher L. ; Dewal, Mahender B. ; Nekongo, Emmanuel E. ; Santiago, Sebasthian ; Lu, Nancy B. ; Levine, Stuart S. ; Shoulders, Matthew D.
• Description:
  Proteostasis in the cytosol is governed by the heat shock response. The master regulator of the heat shock response, heat shock factor 1 (HSF1), and key chaperones whose levels are HSF1-regulated have emerged as high-profile targets for therapeutic applications ranging from protein misfolding-related disorders to cancer. Nonetheless, a generally applicable methodology to selectively and potently inhibit endogenous HSF1 in a small molecule-dependent manner in disease model systems remains elusive. Also problematic, the administration of even highly selective chaperone inhibitors often has the side effect of activating HSF1 and thereby inducing a compensatory heat shock response. Herein, we report a ligand-regulatable, dominant negative version of HSF1 that addresses these issues. Our approach, which required engineering a new dominant negative HSF1 variant, permits dosable inhibition of endogenous HSF1 with a selective small molecule in cell-based model systems of interest. The methodology allows us to uncouple the pleiotropic effects of chaperone inhibitors and environmental toxins from the concomitantly induced compensatory heat shock response. Integration of our method with techniques to activate HSF1 enables the creation of cell lines in which the cytosolic proteostasis network can be up- or down-regulated by orthogonal small molecules. Selective, small molecule-mediated inhibition of HSF1 has distinctive implications for the proteostasis of both chaperone-dependent globular proteins and aggregation-prone intrinsically disordered proteins. Altogether, this work provides critical methods for continued exploration of the biological roles of HSF1 and the therapeutic potential of heat shock response modulation.
• Subjects:
  Arsenite Article Chaperone Destabilized Domain DNA-Binding Proteins Flow Cytometry Gene Expression Regulation Heat Shock Response Heat Shock Transcription Factors HEK293 Cells HSF1 HSP90 Inhibition Humans Immunoblotting Microarray Analysis Proteostasis Real-Time Polymerase Chain Reaction Small Molecule Libraries Transcription Factors

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• Source:
  ACS Chem Biol. 11(1):200-210
• Pubmed ID:
  26502114
• Pubmed Central ID:
  PMC4891198
• Document Type:
  Journal Article
• Funding:
  DP2 GM119162/GM/NIGMS NIH HHS/United States ; P30 ES002109/ES/NIEHS NIH HHS/United States ; 1DP2GM119162/DP/NCCDPHP CDC HHS/United States ; P30-ES002109/ES/NIEHS NIH HHS/United States
• Volume:
  11
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:78f7fd3e2c32921b14889a312a1eb48d14bfe64fb4e3206e127d2990f7c714dd
• Download URL:
  https://stacks.cdc.gov/view/cdc/39794/cdc_39794_DS1.pdf
• File Type:
  [PDF - 1.32 MB ]