Chaperone co-inducer BGP-15 inhibits histone deacetylases and enhances the heat shock response through increased chromatin accessibility

Marek A Budzyński, Tim Crul, Samu V Himanen, Noemi Toth, Ferenc Otvos, Lea Sistonen, Laszlo Vigh

Research output: Contribution to journalArticleScientificpeer-review


Defects in cellular protein homeostasis are associated with many severe and prevalent pathological conditions such as neurodegenerative diseases, muscle dystrophies, and metabolic disorders. One way to counteract these defects is to improve the protein homeostasis capacity through induction of the heat shock response. Despite numerous attempts to develop strategies for chemical activation of the heat shock response by heat shock transcription factor 1 (HSF1), the underlying mechanisms of drug candidates' mode of action are poorly understood. To lower the threshold for the heat shock response activation, we used the chaperone co-inducer BGP-15 that was previously shown to have beneficial effects on several proteinopathic disease models. We found that BGP-15 treatment combined with heat stress caused a substantial increase in HSF1-dependent heat shock protein 70 (HSPA1A/B) expression already at a febrile range of temperatures. Moreover, BGP-15 alone inhibited the activity of histone deacetylases (HDACs), thereby increasing chromatin accessibility at multiple genomic loci including the stress-inducible HSPA1A. Intriguingly, treatment with well-known potent HDAC inhibitors trichostatin A and valproic acid enhanced the heat shock response and improved cytoprotection. These results present a new pharmacological strategy for restoring protein homeostasis by inhibiting HDACs, increasing chromatin accessibility, and lowering the threshold for heat shock response activation.

Original languageEnglish
Pages (from-to)717-728
Number of pages12
JournalCell Stress and Chaperones
Issue number5
Publication statusPublished - Sept 2017
MoE publication typeA1 Journal article-refereed


  • Animals
  • Carrier Proteins/metabolism
  • Cell Line
  • Cell Survival/drug effects
  • Chromatin/metabolism
  • Chromatin Immunoprecipitation
  • Co-Repressor Proteins
  • HSP40 Heat-Shock Proteins/chemistry
  • HSP70 Heat-Shock Proteins/chemistry
  • Heat Shock Transcription Factors/genetics
  • Heat-Shock Response/drug effects
  • Histone Deacetylase Inhibitors/pharmacology
  • Histone Deacetylases/chemistry
  • Intracellular Signaling Peptides and Proteins/metabolism
  • Mice
  • Molecular Chaperones
  • Nuclear Proteins/metabolism
  • Oximes/pharmacology
  • Piperidines/pharmacology
  • Protein Binding
  • Receptor, Notch4/metabolism


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