Trends in Cell Biology
Research FocusModulating molecular chaperone Hsp90 functions through reversible acetylation
Introduction
The molecular chaperone complex containing the heat-shock protein 90 (Hsp90) is essential for the stability and function of ‘client proteins’ necessary for cellular homeostasis 1, 2, 3. Using the glucocorticoid receptor (GR) as a model client protein, Kovacs et al. have demonstrated that Hsp90 activity is regulated by reversible acetylation, a posttranslational modification often associated with histones and chromatin and an important mechanism by which protein activities are regulated [4].
Section snippets
Protein acetylation
Posttranslational modifications such as acetylation can affect protein function, including cellular distribution and ability to interact with other proteins, DNA, RNA and cofactors. These protein–protein interactions are mediated by an acetyl-lysine recognition module (bromodomain) found in an increasing number of proteins [5]. Acetylation is a reversible modification mediated by opposing actions of acetyltransferases (HATs) and deacetylases (HDACs) 5, 6. The best-characterized effects of
Maturation of the glucocorticoid receptor
Hsp90 associates with a variety of co-chaperones in an ATP-dependent manner to facilitate proper stability and function of client proteins such as the GR [1]. The GR is a ligand-dependent transcription factor that regulates target gene expression, resulting in a broad range of biological responses. In the absence of ligand, the GR resides in the cytoplasm, in association with the Hsp90 chaperone complex (Figure 1). Association with the chaperone complex is necessary for the conversion of the GR
Hsp90 regulation by HDAC6
Two recent studies have identified HDAC6 as a regulator of Hsp90 4, 12. The work by Yao and colleagues, the focus of this article, has begun to elucidate the mechanism(s) by which Hsp90 regulates ligand-dependent activation of the GR [4]. This study demonstrated a direct physical interaction between HDAC6 and Hsp90. In addition to the deacetylase activity, which occurs through two catalytic domains (one of them being a tubulin deacetylase domain), HDAC6 has a ubiquitin binding activity mediated
Concluding remarks
Identification of HDAC6-mediated deacetylation as a regulator of Hsp90 function provides another target for therapeutics and is an important contribution to understanding the biological function of Hsp90 [11]. Maintaining the equilibrium between assembly and disassembly of the molecular chaperone complex is likely to be important for proper progression of cellular reactions. It is evident that Hsp90 acetylation status is dynamic, as demonstrated by the increased acetylation of Hsp90 upon
Acknowledgements
We thank Paul Wade, Bonnie Deroo and H. Karimi Kinyamu for critical reading of the manuscript. We apologize to those authors whose relevant work could not be cited owing to reference limitations. This research was supported (in part) by the Intramural Research Program of the NIH and NIEHS.
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Curriculum vitae of HDAC6 in solid tumors
2023, International Journal of Biological MacromoleculesFlavones and flavonols may have clinical potential as CK2 inhibitors in cancer therapy
2020, Medical HypothesesCitation Excerpt :A corollary of this consideration, however, is that measurement of CK2 activity in healthy tissues following oral administration of flavones/flavonols may underestimate the capacity of these agents to inhibit CK2 within tumors. In light of the fact that inhibition of the chaperoning function of Hsp90-Cdc37 plays a key role in the cancer-retardant efficacy of CK2 inhibitors, it is pertinent to note that acetylation of Hsp90 notably reduces its chaperoning activity [175–179]. The cytosolic deacetylase HDAC6 targets these acetylations of Hsp90, restoring its activity.
Identification of 20(R, S)-protopanaxadiol and 20(R, S)-protopanaxatriol for potential selective modulation of glucocorticoid receptor
2019, Food and Chemical ToxicologyCitation Excerpt :These chaperone proteins maintain GR in an inactive conformation that allows it to bind ligands with high affinity (Ng et al., 2017; Ranhotra and Sharma, 2001). Upon ligand binding, GR dissociates from chaperone proteins, dimerizes and translocates into the nucleus, where it binds glucocorticoid-responsive element (GRE) in the promoter to induce transcription (Aoyagi and Archer, 2005). Although glucocorticoids are widely used as anti-inflammatory drugs in clinical practice, they are often accompanied by a series of adverse effects, such as osteoporosis, muscle atrophy, and type 2 diabetes (Potamitis et al., 2019).
Regulation of the Hsp90 system
2018, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :While evidence for Cdc37 phosphorylation is furthest ahead, phosphorylation sites on other cofactors are also getting identified and await their biochemical characterization. Beyond phosphorylation, Hsp90's activity is directly regulated by reversible acetylation mediated by histone acetyltransferases (HAT) and histone deacetylases (HDAC6) [57,58]. Detailed analyses, using HDAC-inhibitors, revealed that under basal condition, acetylated Hsp90s form complexes with their co-chaperones Hop, Hsp70 and Hsp40.