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

Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
Molecular Cell (Impact Factor: 14.02). 06/2005; 18(5):601-7. DOI: 10.1016/j.molcel.2005.04.021
Source: PubMed


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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    • "HDAC6 is a class IIb HDAC with a structure similar to HDAC9; however , HDAC6 primarily resides in the cytoplasm. Substrates of HDAC6 include α-tubulin and Hsp90, which become deacetylated when HDAC6 catalyzes the removal of acetyl groups [25] [30]. We investigated the level of HDAC6 expression in immune cells isolated from early-and late-disease lupus-prone mice due to the role of HDAC6 in cell development and regulation of gene transcription. "
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    ABSTRACT: Prior studies have shown that pan-HDAC inhibition can decrease disease in lupus mice; however, the mechanisms(s) remain to be elucidated. MRL/MpJ-Fas(lpr) (MRL/lpr) mice develop a lupus-like disease characterized by anti-dsDNA production, lymphoproliferation, and immune complex-mediated glomerulonephritis. Early- and late-disease (12 and 20weeks-of-age respectively) female MRL/lpr mice were compared to age-matched, healthy C57BL/6 mice for HDAC expression and activity in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells. We found that HDAC6 was significantly overexpressed in B cells, splenic T cells and glomerular cells, whereas HDAC9 expression was significantly increased in splenic T cells, BM B cells and glomerular cells. Due to the overexpression of HDAC6, we tested whether treatment with a selective HDAC6 inhibitor (ACY-738) or a pan-HDAC inhibitor (TsA) would decrease HDAC activity. ACY-738 significantly reduced cytoplasmic HDAC activity whereas TsA significantly decreased both nuclear and cytoplasmic HDAC activity. In vitro studies in mesangial cells showed that ACY-738 increased α-tubulin and Hsp90 acetylation resulting in decreased nuclear activation of NF-κB. Treatment of pre-B cells with ACY-738 decreased the Bcl-2:Bax ratio leading to a pro-apoptotic environment. These results suggest that increased HDAC6 expression and activity contribute to SLE pathogenesis, and isoform-selective HDAC inhibitors may prove beneficial in the treatment of SLE by acetylating key signaling and transcription factors in inflammation and cell activation.
    International Immunopharmacology 10/2015; DOI:10.1016/j.intimp.2015.10.006 · 2.47 Impact Factor
    • "plays a more important role in facilitating HIF-1a folding in response to hypoxic stress. HDAC6 inhibtion was proposed to increase the acetylation level of Hsp90, thus impairing Hsp90 function [Kovacs et al., 2005; Fath et al., 2006]. However, romidepsin (FK228,depsipeptide), an HDAC inhibitor that has very weak repressive effect on HDAC6, effectively destabilizes HIF-1a, making it possible that it also destabilizes HIF-1a through inhibiting HDAC5 or HDAC4, leading to Hsp70 hyperacetylation [Wang et al., 2007; To et al., 2011]. "
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    ABSTRACT: HIF-1 activation has been well known as an adaptive strategy to hypoxia. Recently it became clear that hypoxia was often accompanied by insufficient supply of glucose or amino acids as a common result of poor circulation that frequently occurs in solid tumors and ischemic lesions, creating a mixed nutrient insufficiency. In response to nutrient insufficiency, stressed cells elicit survival strategies including activation of AMPK and HIF-1 to cope with the stress. Particularly, in solid tumors, HIF-1 promotes cell survival and migration, stimulates angiogenesis, and induces resistance to radiation and chemotherapy. Interestingly, radiation and some chemotherapeutics are reported to trigger the activation of AMPK. Here we discuss the recent advances that may potentially link the stress responsive mechanisms including AMPK activation, ATF4 activation and the enhancement of Hsp70/Hsp90 function to HIF-1 activation. Potential implication and application of the stress-facilitated HIF-1 activation in solid tumors and ischemic disorders will be discussed. A better understanding of HIF-1 activation in cells exposed to stresses is expected to facilitate the design of therapeutic approaches that specifically modulate cell survival strategy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Biochemistry 07/2015; DOI:10.1002/jcb.25283 · 3.26 Impact Factor
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    • "To this purpose, it should be highlighted that the constitutive expression of GR receptor, being a complexant of the Hsp90 protein (Cadepond et al. 1991; Kovacs et al. 2005), may lead to a modification of the homeostasis of such an important protein. (2) The developmental aspects of intracellular targeting of the GR protein in different plant tissue are still poorly understood, making it difficult to recognize between the effects of the GR protein activated by steroids and the unknown targeting of the GR protein within the cell. "
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    ABSTRACT: The present study reports evidence of the pleiotropic effects caused by the insertion of the rat glucocorticoid receptor (GR) into the genome of Nicotiana langsdorffii. Transgenic N. langsdorffii-GR plants and the wild-type genotypes were analysed for their phenotypic and physiological characteristics. The integration of the GR gene affected flowering, growth habit, leaf morphology and stomatal pattern. Furthermore, GR plants showed an increased tolerance to heavy metal, drought and heat stress as evidenced by electrolyte leakage and by cell dedifferentiation and differentiation capability after recovery from stress treatments. We also monitored the establishment of the beneficial symbiosis between transgenic plants and the mycorrhizal fungus Funneliformis mosseae whose presymbiotic growth was significantly reduced by root exudates of N. langsdorffii-GR plants. The observed pleiotropic responses of transgenic plants may be a consequence of the hormonal imbalance, putatively due to the interaction of the GR receptor with the host genetic background. Our findings suggest that N. langsdorffii-GR plants can be used as a functional model system for the study of plant responses to a series of environmental stimuli.
    Plant Biotechnology Reports 07/2015; 9(4). DOI:10.1007/s11816-015-0358-3 · 1.19 Impact Factor
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