HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor
HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor
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DOI：
10.1016/j.molcel.2005.04.021
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发表时间：
2005-05-27
期刊：
影响因子：
16
通讯作者：
Yao, TP
中科院分区：
文献类型：
--
作者：
Kovacs, JJ;Murphy, PJM;Yao, TP
分子伴侣热休克蛋白90 （Hsp90）及其辅助伴侣蛋白通过促进客户蛋白（包括类固醇激素受体和选定的激酶）的结构成熟和复杂组装而起作用。通过促进这些信号蛋白的活性和稳定性，Hsp90已成为细胞信号传导的关键调节剂。在这里，我们提供的证据表明，Hsp90伴侣活性受可逆乙酰化和去乙酰化酶HDAC6控制。我们发现HDAC6具有Hsp90去乙酰化酶的功能。HDAC6失活导致Hsp90超乙酰化，其与重要的伴侣蛋白p23分离，并失去伴侣蛋白活性。在hdac6缺陷细胞中，依赖hsp90的糖皮质激素受体（GR）成熟受到损害，导致GR在配体结合、核易位和转录激活方面存在缺陷。我们的研究结果确定Hsp90是HDAC6的靶标，并表明可逆乙酰化是调节Hsp90伴侣复合物活性的独特机制。
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.