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HDAC6 Regulates Hsp90 Acetylation and Chaperone-Dependent Activation of Glucocorticoid Receptor
Open accessAbstract
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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“To further investigate the potential of acetylation to inhibit Hsp90 function, we used trichostatin A (TSA), which was shown to induce acetylation of Hsp90 in eukaryotes (17–20).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [18]
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Self-citationA high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors
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Self-citationFolding of the Glucocorticoid Receptor by the Heat Shock Protein (hsp) 90-based Chaperone Machinery
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Self-citationActive maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm
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Anticancer activities of histone deacetylase inhibitors
Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2133 · Cited by 2,919
Haberland, M., Montgomery, R. L., & Olson, E. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2485 · Cited by 2,600
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer
Minucci, S., & Pelicci, P. G. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1779 · Cited by 2,234
Energy Metabolism in the Liver
Rui, L. (2014) · Comprehensive physiology · doi:10.1002/cphy.c130024 · Cited by 2,401
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
Taipale, M., Jarosz, D. F., & Lindquist, S. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2918 · Cited by 1,818
Metadata
- 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
- bronze
- doi.org
- Licence
- 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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