Modulation of Histone Deacetylase 6 (HDAC6) Nuclear Import and Tubulin Deacetylase Activity through Acetylation
Modulation of Histone Deacetylase 6 (HDAC6) Nuclear Import and Tubulin Deacetylase Activity through Acetylation
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DOI：
10.1074/jbc.m112.371120
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发表时间：
2012-08-17
影响因子：
4.8
通讯作者：
Qiu, Yi
中科院分区：
文献类型：
--
作者：
Liu, Yuanjing;Peng, Lirong;Qiu, Yi
组蛋白乙酰基转移酶和脱乙酰基酶（HDAC）对组蛋白和非组蛋白的可逆乙酰化在真核细胞的许多细胞过程中起着关键作用。HDAC 6是一种独特的组蛋白脱乙酰基酶，具有两个脱乙酰基酶结构域和一个C-末端锌指结构域。HDAC 6主要存在于细胞质中，并调节许多重要的生物学过程，包括细胞迁移和错误折叠蛋白的降解。HDAC 6也被证明定位于细胞核中以调节转录。然而，HDAC 6如何在细胞核和细胞质之间穿梭在很大程度上是未知的。此外，尚不清楚HDAC 6酶活性如何调节。在这里，我们表明，HDAC 6可以乙酰化的p300上的5个簇的赖氨酸残基。乙酰化赖氨酸的一个簇（位点B）位于N-末端核定位信号区。将位点B中的这些赖氨酸残基转化为谷氨酰胺以模拟乙酰化赖氨酸。突变显着降低HDAC 6微管蛋白脱乙酰酶活性和进一步损害细胞运动，但组蛋白脱乙酰酶活性没有影响。更有趣的是，这些突变通过阻断与核输入蛋白importin-alpha的相互作用将HDAC 6保留在细胞质中。HDAC 6通过乙酰化保留在细胞质中最终影响组蛋白去乙酰化。因此，我们得出结论，乙酰化是一个重要的翻译后修饰，调节HDAC 6微管蛋白脱乙酰酶活性和核输入。
The reversible acetylation of histones and non-histone proteins by histone acetyltransferases and deacetylases (HDACs) plays a critical role in many cellular processes in eukaryotic cells. HDAC6 is a unique histone deacetylase with two deacetylase domains and a C-terminal zinc finger domain. HDAC6 resides mainly in the cytoplasm and regulates many important biological processes, including cell migration and degradation of misfold proteins. HDAC6 has also been shown to localize in the nucleus to regulate transcription. However, how HDAC6 shuttles between the nucleus and cytoplasm is largely unknown. In addition, it is not clear how HDAC6 enzymatic activity is modulated. Here, we show that HDAC6 can be acetylated by p300 on five clusters of lysine residues. One cluster (site B) of acetylated lysine is in the N-terminal nuclear localization signal region. These lysine residues in site B were converted to glutamine to mimic acetylated lysines. The mutations significantly reduced HDAC6 tubulin deacetylase activity and further impaired cell motility, but had no effect on histone deacetylase activity. More interestingly, these mutations retained HDAC6 in the cytoplasm by blocking the interaction with the nuclear import protein importin-alpha. The retention of HDAC6 in the cytoplasm by acetylation eventually affects histone deacetylation. Thus, we conclude that acetylation is an important post-translational modification that regulates HDAC6 tubulin deacetylase activity and nuclear import.