CaM kinase II selectively signals to histone deacetylase 4 during cardiornyocyte hypertrophy
CaM kinase II selectively signals to histone deacetylase 4 during cardiornyocyte hypertrophy
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DOI：
10.1172/jci27438
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发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
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作者：
Backs, Johannes;Song, Kunhua;Olson, Eric N.
IIa类组蛋白脱乙酰酶（HDAC）调节多种细胞过程，包括心脏生长、骨发育和骨骼肌纤维类型的特化。多种丝氨酸/苏氨酸激酶通过共同丝氨酸残基的磷酸化来控制这些HDAC的亚细胞定位，但某些IIa类HDAC是否选择性地响应于特定激酶尚未确定。在这里，我们表明，钙/钙调蛋白依赖性激酶11（CaMKII）信号特异性HDAC 4结合到一个独特的对接位点，是不存在于其他IIa类HDACs。通过CaMK II磷酸化HDAC 4促进核输出并阻止HDAC 4的核输入，从而使HDAC靶基因去阻遏。在心肌细胞中，HDAC 4的CaMKII磷酸化导致肥大性生长，这可以被信号抗性HDAC 4突变体阻断。这些发现揭示了HDAC 4在CaMKII信号通路中的核心作用，并对多种细胞类型中通过钙信号传导控制基因表达具有影响。
Class IIa histone deacetylases (HDACs) regulate a variety of cellular processes, including cardiac growth, bone development, and specification of skeletal muscle fiber type. Multiple serine/threonine kinases control the subcellular localization of these HDACs by phosphorylation of common serine residues, but whether certain class IIa HDACs respond selectively to specific kinases has not been determined. Here we show that calcium/ calmodulin-dependent kinase 11 (CaMKII) signals specifically to HDAC4 by binding to a unique docking site that is absent in other class IIa HDACs. Phosphorylation of HDAC4 by CaMKII promotes nuclear export and prevents nuclear import of HDAC4, with consequent derepression of HDAC target genes. In cardiomyocytes, CaMKII phosphorylation of HDAC4 results in hypertrophic growth, which can be blocked by a signal-resistant HDAC4 mutant. These findings reveal a central role for HDAC4 in CaMKII signaling pathways and have implications for the control of gene expression by calcium signaling in a variety of cell types.