Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis
Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis
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DOI：
10.1091/mbc.e03-08-0624
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发表时间：
2004-06-01
影响因子：
3.3
通讯作者：
Brancolini, C
中科院分区：
文献类型：
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作者：
Paroni, G;Mizzau, M;Brancolini, C
组蛋白去乙酰化酶（HDAC）作为转录辅阻遏物复合物的一部分，是基因表达的重要调控因子。在这里，我们证明，半胱天冬酶可以抑制肌细胞增强因子（MEF）2C转录因子的活性，通过调节HDAC 4处理。HDAC 4的裂解发生在Asp 289处，并将位于细胞质中的羧基末端片段与积累到细胞核中的氨基末端片段分离。在细胞核中，半胱天冬酶产生的HDAC 4片段能够以半胱天冬酶-9依赖性方式触发细胞色素c从线粒体释放和细胞死亡。半胱天冬酶切割的HDAC 4的氨基末端片段作为转录因子MEF 2C的强阻遏物，独立于HDAC结构域。从HDAC 4的半胱天冬酶切割片段中去除氨基酸166-289消除了其抑制MEF 2转录和诱导细胞死亡的能力。Caspase-2和caspase-3在体外切割HDAC 4，而caspase-3在紫外线诱导的细胞凋亡期间对于体内切割HDAC 4至关重要。在UV照射后，GFP-HDAC 4在回缩反应之前恰好/立即易位到细胞核中，但明显在核碎裂之前。总之，我们的数据表明，半胱天冬酶可以通过HDAC 4的蛋白水解加工特异性地调节基因抑制和细胞凋亡。
Histone deacetylases (HDACs) are important regulators of gene expression as part of transcriptional corepressor complexes. Here, we demonstrate that caspases can repress the activity of the myocyte enhancer factor (MEF)2C transcription factor by regulating HDAC4 processing. Cleavage of HDAC4 occurs at Asp 289 and disjoins the carboxy-terminal fragment, localized into the cytoplasm, from the amino-terminal fragment, which accumulates into the nucleus. In the nucleus, the caspase-generated fragment of HDAC4 is able to trigger cytochrome c release from mitochondria and cell death in a caspase-9-dependent manner. The caspase-cleaved amino-terminal fragment of HDAC4 acts as a strong repressor of the transcription factor MEF2C, independently from the HDAC domain. Removal of amino acids 166-289 from the caspase-cleaved fragment of HDAC4 abrogates its ability to repress MEF2 transcription and to induce cell death. Caspase-2 and caspase-3 cleave HDAC4 in vitro and caspase-3 is critical for HDAC4 cleavage in vivo during UV-induced apoptosis. After UV irradiation, GFP-HDAC4 translocates into the nucleus coincidentally/immediately before the retraction response, but clearly before nuclear fragmentation. Together, our data indicate that caspases could specifically modulate gene repression and apoptosis through the proteolyic processing of HDAC4.