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

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.

Histone deacetylase inhibitors: molecular mechanisms of action

“…HDAC6 can not only bind both mono and poly-ubiquitinated proteins but also promote its own mono-ubiquitination. Specific inhibition of HDAC6 activity or its downregulation by siRNA increases a-tubulin and HSP90 acetylation, which reduces cellular motility, and induces HSP90 client proteins degradation, cell growth inhibition and cell death (Bali et al, 2005;Kovacs et al, 2005). Acetylated HSP90 cannot form stable complex with client proteins and its deacetylation by HDAC6 is required to regenerate functional HSP90 (Aoyagi and Archer, 2005).…”

“…As indicated above, this chaperone protein is essential for the stability and function of many client proteins, including steroid hormone receptors and protein kinases, that are crucial for numerous cell signaling processes and cellular homeostasis (Solit and Rosen, 2006). Recent studies have demonstrated both a direct physical interaction between HDAC6 and HSP90, and HDAC6 as a regulator of HSP90 activity, through its deacetylation (Bali et al, 2005;Kovacs et al, 2005). Considering the number of HSP90 client proteins, many molecular alterations can be anticipated as a result of HSP90 inactivation through HDAC6 inhibition by HDACi, or its downregulation by HDAC6 siRNA.…”

Conformational dynamics of the molecular chaperone Hsp90

“…While it is clear that acetylation and phosphorylation are important aspects of Hsp90's in vivo function, the precise role of these modifications in the chaperone cycle is not well understood. Hyperactylation of Hsp90 disrupts the binding of both client proteins and co-chaperones (Kekatpure et al, 2009;Kovacs et al, 2005;Scroggins et al, 2007;Yu et al, 2002). Regulation of Hsp90's acetylation status occurs primarily through HDAC6 which binds directly to Hsp90 (Kekatpure et al, 2009), and inhibition of HDAC6 leads to the hyperacetylation of Hsp90 (Yu et al, 2002).…”

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

“…Of the known substrates of HDAC6, Hsp90 may be linked with the HDAC6-mediated regulation of mitochondrial metabolic activity. Inactivation of HDAC6 leads to hyperacetylation of Hsp90 and instability of its client proteins [6,7]. Interestingly, Kang et al have found that an abundant pool of Hsp90 localizes to mitochondria in various tumor cells and regulates mitochondrial integrity [21].…”

“…Early studies found that HDAC6-mediated a-tubulin deacetylation destabilizes dynamic microtubules [3] and promotes an increase in cell motility [4,5]. In addition to a-tubulin, several cytoplasmic proteins including Hsp90 [6,7], cortactin [8], b-catenin [9], peroxiredoxins I and II [10], and Ku70 [11] are regulated in a HDAC6-mediated deacetylation-dependent manner. Strong ubiquitin binding activity [12,13] further adds to the multifunctionality of HDAC6, enabling the regulation of many important processes including cell migration, cell stress response to the cytotoxic accumulation of protein aggregates, and immune synapse formation [1,2].…”