Lee Heehyoung, Rezai-Zadeh Natalie, Seto Edward
H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Mol Cell Biol. 2004 Jan;24(2):765-73. doi: 10.1128/MCB.24.2.765-773.2004.
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from lysine residues of histone and nonhistone proteins. Recent studies suggest that they are key regulators of many cellular events, including cell proliferation and cancer development. Human class I HDACs possess homology to the yeast RPD3 protein and include HDAC1, HDAC2, HDAC3, and HDAC8. While HDAC1, HDAC2, and HDAC3 have been characterized extensively, almost nothing is known about HDAC8. Here we report that HDAC8 is phosphorylated by cyclic AMP-dependent protein kinase A (PKA) in vitro and in vivo. The PKA phosphoacceptor site of HDAC8 is Ser(39), a nonconserved residue among class I HDACs. Mutation of Ser(39) to Ala enhances the deacetylase activity of HDAC8. In contrast, mutation of Ser(39) to Glu or induction of HDAC8 phosphorylation by forskolin, a potent activator of adenyl cyclase, decreases HDAC8's enzymatic activity. Remarkably, inhibition of HDAC8 activity by hyperphosphorylation leads to hyperacetylation of histones H3 and H4, suggesting that PKA-mediated phosphorylation of HDAC8 plays a central role in the overall acetylation status of histones.
组蛋白去乙酰化酶（HDACs）是一类催化从组蛋白和非组蛋白的赖氨酸残基上去除乙酰基的酶。最近的研究表明，它们是许多细胞事件的关键调节因子，包括细胞增殖和癌症发展。人类I类HDACs与酵母RPD3蛋白具有同源性，包括HDAC1、HDAC2、HDAC3和HDAC8。虽然HDAC1、HDAC2和HDAC3已被广泛研究，但关于HDAC8几乎一无所知。在此我们报告，HDAC8在体外和体内均被环磷酸腺苷依赖性蛋白激酶A（PKA）磷酸化。HDAC8的PKA磷酸化位点是Ser(39)，这是I类HDACs中一个非保守残基。将Ser(39)突变为丙氨酸可增强HDAC8的去乙酰化酶活性。相反，将Ser(39)突变为谷氨酸或用强效腺苷酸环化酶激活剂福斯可林诱导HDAC8磷酸化，会降低HDAC8的酶活性。值得注意的是，HDAC8过度磷酸化导致的活性抑制会导致组蛋白H3和H4的过度乙酰化，这表明PKA介导的HDAC8磷酸化在组蛋白的整体乙酰化状态中起核心作用。
