Acute β-Adrenergic Activation Triggers Nuclear Import of Histone Deacetylase 5 and Delays Gq-induced Transcriptional Activation
Acute β-Adrenergic Activation Triggers Nuclear Import of Histone Deacetylase 5 and Delays Gq-induced Transcriptional Activation
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DOI：
10.1074/jbc.m112.382358
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发表时间：
2013-01-04
影响因子：
4.8
通讯作者：
Bers, Donald M.
中科院分区：
文献类型：
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作者：
Chang, Chia-Wei Jenny;Lee, Linda;Bers, Donald M.
在血流动力学应激过程中，儿茶酚胺和神经体液刺激可诱导G(Q)偶联受体和β-肾上腺素能受体(β-AR)的共同激活，从而导致心脏重构。组蛋白脱乙酰基酶5(HDAC5)是一种转录抑制因子，由于其在胎儿基因标志物的表观遗传调控中的作用，在应激信号传递过程中起着至关重要的作用。在成人心肌细胞中，它在急性和慢性β-AR刺激过程中的调节以及它与G(Q)信号的交叉相互作用还知之甚少。在这里，我们在HDAC5的核质穿梭水平上评估了G(Q)驱动和β-AR介导的信号之间的潜在串扰。我们显示了GFP标记的野生型HDAC5或突变体(S279A和S279D)对β-AR或G(Q)激动剂的反应。异丙肾上腺素(ISO)或PKA的激活导致HDAC5的核聚集，而不是由钙-钙调蛋白激酶II和蛋白激酶D驱动的核输出。此外，在急性ISO/PKA信号下，HDAC5的核聚集依赖于Ser-279的磷酸化，并可以阻止G(Q)介导的核HDAC5输出。有趣的是，在慢性激活PKA后，G(Q)诱导的输出的衰减被消除，但核HDAC5仍然升高。最后，在心力衰竭兔模型的成年心肌细胞中，研究了慢性β-AR信号对HDAC5转位的影响，在该模型中，ISO诱导的核输入被消融，但G(Q)激动剂介导的输出被保留。急性β-AR/PKA激活通过延迟G(Q)介导的转录激活来保护肥大信号。这是一个关键的生理控制开关，在更严重的压力下，如心力衰竭，允许通过HDAC5核输出进行基因重编程。
During hemodynamic stress, catecholamines and neurohumoral stimuli may induce co-activation of G(q)-coupled receptors and beta-adrenergic receptors (beta-AR), leading to cardiac remodeling. Dynamic regulation of histone deacetylase 5 (HDAC5), a transcriptional repressor, is crucial during stress signaling due to its role in epigenetic control of fetal gene markers. Little is known about its regulation during acute and chronic beta-AR stimulation and its cross-interaction with G(q) signaling in adult cardiac myocytes. Here, we evaluate the potential cross-talk between G(q)-driven and beta-AR mediated signaling at the level of nucleocytoplasmic shuttling of HDAC5. We show the translocation of GFP-tagged wild type HDAC5 or mutants (S279A and S279D) in response to beta-AR or G(q) agonists. Isoproterenol (ISO) or PKA activation results in strong nuclear accumulation of HDAC5 in contrast to nuclear export driven by Ca2+-calmodulin protein kinase II and protein kinase D. Moreover, nuclear accumulation of HDAC5 under acute ISO/PKA signaling is dependent on phosphorylation of Ser-279 and can block subsequent G(q)-mediated nuclear HDAC5 export. Intriguingly, the attenuation of G(q)-induced export is abolished after chronic PKA activation, yet nuclear HDAC5 remains elevated. Last, the effect of chronic beta-AR signaling on HDAC5 translocation was examined in adult myocytes from a rabbit model of heart failure, where ISO-induced nuclear import is ablated, but G(q)-agonist mediated export is preserved. Acute beta-AR/PKA activation protects against hypertrophic signaling by delaying G(q)-mediated transcriptional activation. This serves as a key physiological control switch before allowing genetic reprogramming via HDAC5 nuclear export during more severe stress, such as heart failure.