Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility.
Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility.
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DOI：
10.1091/mbc.e10-07-0616
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发表时间：
2011-01-15
影响因子：
3.3
通讯作者：
Brancolini C
中科院分区：
文献类型：
--
作者：
Cernotta N;Clocchiatti A;Florean C;Brancolini C
组蛋白脱乙酰酶 4 (HDAC4) 控制多种细胞反应并受到多个级别的调节。此处显示 HDAC4 以生长因子和 GSK3β 依赖性方式受到蛋白酶体的调节。 HDAC4 的降解可能导致细胞周期 G0 期细胞中观察到的随机细胞运动减弱。 HDAC4（组蛋白脱乙酰酶 4）属于 IIa 类组蛋白脱乙酰酶，它是基因表达的重要调节因子，控制多效性细胞功能。在这里，我们表明，除了明确的核/细胞质穿梭之外，HDAC4 活性还受到泛素-蛋白酶体系统的调节。血清饥饿会引起非转化细胞中 HDAC4 的多聚泛素化和降解。 PEST1 序列中丝氨酸 298 的磷酸化在控制 HDAC4 稳定性中起着重要作用。丝氨酸 298 位于糖原合酶激酶 3β 共有序列内，去除生长因子无法触发缺乏该激酶的细胞中的 HDAC4 降解。 GSK3β在体外可以磷酸化HDAC4，丝氨酸302的磷酸化似乎起到了引发磷酸化的作用。我们还发现 HDAC4 可能通过调节 KLF2 转录来调节随机细胞运动。细胞凋亡、自噬、细胞增殖和生长停滞不受 HDAC4 的影响。我们的数据表明 HDAC4 降解的调节与生长因子对细胞运动的控制之间存在联系。
Histone deacetylase 4 (HDAC4) controls several cellular responses and is subjected to multiple levels of regulation. Here it is shown that HDAC4 is under the regulation of the proteasome, in a growth factor- and GSK3β-dependent manner. Degradation of HDAC4 could contribute to the attenuation of random cell motility observed in cells in the G0 phase of the cell cycle. HDAC4 (histone deacetylase 4) belongs to class IIa of histone deacetylases, which groups important regulators of gene expression, controlling pleiotropic cellular functions. Here we show that, in addition to the well-defined nuclear/cytoplasmic shuttling, HDAC4 activity is modulated by the ubiquitin–proteasome system. Serum starvation elicits the poly-ubiquitination and degradation of HDAC4 in nontransformed cells. Phosphorylation of serine 298 within the PEST1 sequence plays an important role in the control of HDAC4 stability. Serine 298 lies within a glycogen synthase kinase 3β consensus sequence, and removal of growth factors fails to trigger HDAC4 degradation in cells deficient in this kinase. GSK3β can phosphorylate HDAC4 in vitro, and phosphorylation of serine 302 seems to play the role of priming phosphate. We have also found that HDAC4 modulates random cell motility possibly through the regulation of KLF2 transcription. Apoptosis, autophagy, cell proliferation, and growth arrest were unaffected by HDAC4. Our data suggest a link between regulation of HDAC4 degradation and the control of cell motility as operated by growth factors.