HCMV IE2-mediated inhibition of HAT activity downregulates p53 function
HCMV IE2-mediated inhibition of HAT activity downregulates p53 function
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DOI：
10.1038/sj.emboj.7600239
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发表时间：
2004-06-02
期刊：
影响因子：
11.4
通讯作者：
Juan, LJ
中科院分区：
文献类型：
--
作者：
Hsu, CH;Chang, MDT;Juan, LJ
病毒蛋白靶向细胞组蛋白乙酰转移酶 (HAT) 在病毒相关疾病的发展中非常重要。人巨细胞病毒 (HCMV) 的立即早期 2 蛋白 (IE2) 与肿瘤抑制因子 p53 结合，并通过未知机制使其功能失活。在这里，我们发现 IE2 与 p53 共激活因子、p300 和 CREB 结合蛋白 (CBP) 的 HAT 结构域结合，并阻断它们对组蛋白和 p53 的乙酰转移酶活性。 IE2 上的最小 HAT 失活区域涉及 N 端 98 个氨基酸。 p53 的体内 DNA 结合和 p53 依赖性启动子上的局部组蛋白乙酰化均会被 IE2 降低，但不会被缺乏 HAT 抑制区域的突变型 IE2 蛋白降低。此外，p53 乙酰化位点突变体 K320/373/382R 在体内保留了 DNA 结合和启动子反式激活活性，并且这些效应也被 IE2 抑制。连同只有野生型 IE2 发挥抗凋亡作用的发现一起，我们的结果表明 HCMV IE2 通过抑制 p300/CBP 介导的局部组蛋白乙酰化来下调 p53 依赖性基因激活，并且 IE2 可能具有致癌活性。
Targeting of cellular histone acetyltransferases (HATs) by viral proteins is important in the development of virus-associated diseases. The immediate-early 2 protein (IE2) of human cytomegalovirus ( HCMV) binds to the tumor suppressor, p53, and inactivates its functions by unknown mechanisms. Here, we show that IE2 binds to the HAT domain of the p53 coactivators, p300 and CREB-binding protein (CBP), and blocks their acetyltransferase activity on both histones and p53. The minimal HAT inactivation region on IE2 involves the N-terminal 98 amino acids. The in vivo DNA binding of p53 and local histone acetylation on p53-dependent promoters are all reduced by IE2, but not by mutant IE2 proteins that lack the HAT inhibition region. Furthermore, the p53 acetylation site mutant, K320/373/382R, retains both DNA binding and promoter transactivation activity in vivo and these effects are repressed by IE2 as well. Together with the finding that only wild-type IE2 exerts an antiapoptotic effect, our results suggest that HCMV IE2 downregulates p53-dependent gene activation by inhibiting p300/CBP-mediated local histone acetylation and that IE2 may have oncogenic activity.