Enhancement of stress resilience through histone deacetylase 6-mediated regulation of glucocorticoid receptor chaperone dynamics.
Enhancement of stress resilience through histone deacetylase 6-mediated regulation of glucocorticoid receptor chaperone dynamics.
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DOI：
10.1016/j.biopsych.2014.07.036
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发表时间：
2015-02-15
影响因子：
10.6
通讯作者：
Berton O
中科院分区：
文献类型：
--
作者：
Jochems J;Teegarden SL;Chen Y;Boulden J;Challis C;Ben-Dor GA;Kim SF;Berton O
热休克蛋白90的乙酰化通过糖皮质激素受体（GR）调节下游激素信号，但这种分子机制在应激稳态中的作用仍然知之甚少。我们测试了大脑中Hsp 90的乙酰化是否可以预测和调节社会压力小鼠模型的行为后遗症。将经受慢性社会失败压力（CSDS）的小鼠分层为弹性亚群和脆弱亚群。HPA轴功能检测采用DEX/CRF试验。在中缝背核（DRN）中检测Hsp 90乙酰化、Hsp 90-GR相互作用和GR转位。为了操纵Hsp 90乙酰化，我们抑制了Hdac 6，一种已知的Hsp 90脱乙酰酶或过表达一种模拟Hsp 90在赖氨酸K294处的高乙酰化状态的点突变体。在CSDS后的易感小鼠的DRN中观察到较低的乙酰化Hsp 90，较高的GR-Hsp 90缔合和增强的GR易位。ACY-738，一种Hdac 6选择性抑制剂，导致Hsp 90在脑和神经元培养物中过度乙酰化。在基于细胞的测定中，ACY-738增加了Hsp 90与FKBP 51相对于FKBP 52的相对缔合，并抑制了Hsp 90诱导的GR易位。这种效果被复制过表达的乙酰化模拟点突变的热休克蛋白90。在体内，ACY-738促进了对CSDS的恢复力，并且在中缝神经元中Hsp 90的乙酰化模拟突变体的胡萝卜素选择性病毒过表达再现了ACY-738的抗病毒作用。Hsp 90的超乙酰化是小鼠应激恢复的预测因子和因果分子决定因素。脑渗透剂Hdac 6抑制剂增加Hsp 90乙酰化并调节GR分子伴侣动力学，为减少应激和糖皮质激素的有害社会情感效应提供了一种有前途的策略。
Acetylation of Hsp90 regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis remains poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress. Mice subjected to chronic social defeat stress (CSDS) were stratified into resilient and vulnerable subpopulations. HPA axis function was probed using a DEX/CRF test. Hsp90 acetylation, Hsp90-GR interactions and GR translocation were measured in the dorsal raphe nucleus (DRN). To manipulate Hsp90 acetylation, we pharmacologically inhibited Hdac6, a known deacetylase of Hsp90 or overexpressed a point-mutant that mimics the hyperacetylated state of Hsp90 at lysine K294 Lower acetylated Hsp90, higher GR-Hsp90 association and enhanced GR translocation were observed in DRN of vulnerable mice after CSDS. Administration of ACY-738, an Hdac6-selective inhibitor, led to Hsp90 hyperacetylation in brain and in neuronal culture. In cell-based assays, ACY-738 increased the relative association of Hsp90 with FKBP51 versus FKBP52 and inhibited hormone-induced GR translocation. This effect was replicated by overexpressing the acetylation-mimic point-mutant of Hsp90. In vivo, ACY-738 promoted resilience to CSDS and serotonin-selective viral overexpression of the acetylation-mimic mutant of Hsp90 in raphe neurons reproduced the behaviroral effect of ACY-738. Hyperacetylation of Hsp90 is a predictor and causal molecular determinant of stress resilience in mice. Brain-penetrant Hdac6 inhibitors increase Hsp90 acetylation and modulate GR chaperone dynamics offering a promising strategy to curtail deleterious socioaffective effects of stress and glucocorticoids.
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影响因子：
4.7
作者：
Furay, A. R.;Murphy, E. K.;Herman, J. P.
通讯作者：
Herman, J. P.
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
120.7
作者：
Binder, Elisabeth B.;Bradley, Rebekah G.;Ressler, Kerry J.
通讯作者：
Ressler, Kerry J.
影响因子：
3.7
作者：
Binder, E. B.;Kuenzel, H. E.;Holsboer, F.
通讯作者：
Holsboer, F.
DOI：
10.1073/pnas.0400116101
发表时间：
2004-03-02
影响因子：
11.1
作者：
Elbi, C;Walker, DA;DeFranco, DB
通讯作者：
DeFranco, DB