HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.
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.
Kovacs
Jeffrey J
JJ
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
Murphy
Patrick J M
PJ
Gaillard
Stéphanie
S
Zhao
Xuan
X
Wu
June-Tai
JT
Nicchitta
Christopher V
CV
Yoshida
Minoru
M
Toft
David O
DO
Pratt
William B
WB
Yao
Tso-Pang
TP
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
D005938:Glucocorticoids; D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases