Acetylation of Stat1 modulates NF-κB activity
Acetylation of Stat1 modulates NF-κB activity
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DOI：
10.1101/gad.364306
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发表时间：
2006-02-15
影响因子：
10.5
通讯作者：
Heinzel, T
中科院分区：
文献类型：
--
作者：
Krämer, OH;Baus, D;Heinzel, T
信号分子乙酰化可导致癌细胞凋亡或分化。这些过程的分子机制和介导乙酰基转移或去除的酶的生物学作用目前正在深入研究中。我们的研究表明Stat 1是一种乙酰化蛋白。Stat 1乙酰化依赖于Stat 1相关的组蛋白脱乙酰酶（HDAC）和组蛋白乙酰转移酶（HAT）（如CBP）之间的平衡。值得注意的是，HDAC抑制剂和细胞因子干扰素α改变了这种平衡并诱导Stat 1乙酰化。Statl突变体的分析揭示Lys 410和Lys 413为乙酰化位点。模拟组成性乙酰化或非乙酰化状态的Stat 1突变体的实验表明，只有乙酰化的Stat 1能够与NF-κ B p65相互作用。因此，p65 DNA结合、核定位和抗凋亡NF-κ B靶基因的表达降低。这些发现显示了Statl的乙酰化如何调节NF-κ B活性并因此最终调节细胞凋亡。
Acetylation of signaling molecules can lead to apoptosis or differentiation of carcinoma cells. The molecular mechanisms underlying these processes and the biological role of enzymes mediating the transfer or removal of an acetyl-group are currently under intense investigation. Our study shows that Stat1 is an acetylated protein. Stat1 acetylation depends on the balance between Stat1-associated histone deacetylases (HDACs) and histone acetyltransferases (HATs) such as CBP. Remarkably both inhibitors of HDACs and the cytokine interferon alpha alter this equilibrium and induce Stat1 acetylation. The analysis of Statl mutants reveals Lys 410 and Lys 413 as acetylation sites. Experiments with Statl mutants mimicking either constitutively acetylated or nonacetylated states show that only acetylated Stat1l is able to interact with NF-kappa B p65. As a consequence, p65 DNA binding, nuclear localization, and expression of anti-apoptotic NF-kappa B target genes decrease. These findings show how the acetylation of Statl regulates NF-kappa B activity and thus ultimately apoptosis.