Cited by 1,153Heat shock proteins researchHistone Deacetylase Inhibitors ResearchUbiquitin and proteasome pathways

HDAC6 Regulates Hsp90 Acetylation and Chaperone-Dependent Activation of Glucocorticoid Receptor

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Kovacs, Jeffrey J., Murphy, Patrick J.M., Gaillard, Stéphanie, Zhao, Xuan, Wu, June-Tai, Nicchitta, Christopher V., Yoshida, Minoru, Toft, David O. +2 more·2005·Molecular Cell

Abstract

The molecular chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the activity and stability of these signaling proteins, Hsp90 has emerged as a critical modulator in cell signaling. Here, we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissociation from an essential cochaperone, p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Our results identify Hsp90 as a target of HDAC6 and suggest reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity.

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Crossref · 10.1016/j.molcel.2005.04.021

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Authors
Kovacs, J. J., Murphy, P. J. M., Gaillard, S., Zhao, X., Wu, J.-T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B., & Yao, T.-P.
Affiliations
  • Duke University (US)
  • University of Michigan (US)
  • Japan Science and Technology Agency (JP)
  • Mayo Clinic (US)
Corresponding author
Yao, Tso-Pang
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2005-05
Volume
18
Issue
5
Pages
601-607
ISSN
1097-2765 (ISSN-L)
OpenAlex
W1990011854
Cited by
1,153
References
25
Citations by year
2026: 39 · 2025: 49 · 2024: 44 · 2023: 37 · 2022: 55 · 2021: 48 · 2020: 51 · 2019: 50 · 2018: 49 · 2017: 47 · 2016: 63 · 2015: 69 · 2014: 71 · 2013: 69 · 2012: 59
FWCI
20.58
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Leukemia and Lymphoma Society
  • American Cancer Society (RSG-03-147-01-CSM)
  • National Institutes of Health (DK31573, CA28010)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
HDAC6, HSP90, HSP90 acetylation, glucocorticoid receptor, p23, steroid hormone receptors, nuclear translocation, transcriptional activation, ligand binding
MeSH terms
Histone Deacetylase 6, Acetylation, Animals, Cell Line, Dexamethasone, Glucocorticoids, Histone Deacetylases, Humans, Receptors, Glucocorticoid, Transcription, Genetic, Signal Transduction, HSP90 Heat-Shock Proteins, Mice

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