A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression
A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression
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DOI：
10.1038/nature01648
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发表时间：
2003-06-05
期刊：
影响因子：
64.8
通讯作者：
Baldwin, AS
中科院分区：
文献类型：
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作者：
Anest, V;Hanson, JL;Baldwin, AS
NF-kappaB是一种主要的转录调节因子，参与多种丝氨酸介导的过程，并受到IkappaB激酶复合物（IKK-alpha/beta/gamma）的严格控制。IKK-β和IKK-γ对马槟榔碱诱导的NF-κ B功能至关重要，而IKK-α被认为参与其他调节途径（1-4）。然而，最近的数据表明IKK-α在响应细胞因子治疗的NF-κ B依赖性基因表达中的作用（1，5 -7）。在这里，我们证明细胞因子暴露后IKK-α的核积累，表明这种蛋白质的核功能。与此相一致，染色质免疫沉淀（ChIP）试验表明，IKK-α被招募到NF-κ B调节基因的启动子区的刺激与肿瘤坏死因子-α。值得注意的是，NF-κ B调节的基因表达被IKK-α的丢失抑制，这与组蛋白H3在丝氨酸10上的基因特异性磷酸化的完全丢失相关，这是一种先前与阳性基因表达相关的修饰。此外，我们发现IKK-α可以在体外直接磷酸化组蛋白H3，这表明这种激酶的新底物。我们认为IKK-α是NF-κ B依赖性基因表达的重要调节因子，通过控制细胞因子暴露后启动子相关的组蛋白磷酸化。这些发现为IKK复合物在NF-κ B调控的基因表达中的作用提供了额外的见解。
NF-kappaB is a principal transcriptional regulator of diverse cytokine-mediated processes and is tightly controlled by the IkappaB kinase complex (IKK-alpha/beta/gamma). IKK-beta and IKK-gamma are critical for cytokine-induced NF-kappaB function, whereas IKK-alpha is thought to be involved in other regulatory pathways(1-4). However, recent data suggest a role for IKK-alpha in NF-kappaB-dependent gene expression in response to cytokine treatment(1,5-7). Here we demonstrate nuclear accumulation of IKK-alpha after cytokine exposure, suggesting a nuclear function for this protein. Consistent with this, chromatin immunoprecipitation (ChIP) assays reveal that IKK-alpha was recruited to the promoter regions of NF-kappaB-regulated genes on stimulation with tumour-necrosis factor-alpha. Notably, NF-kappaB-regulated gene expression is suppressed by the loss of IKK-alpha and this correlates with a complete loss of gene-specific phosphorylation of histone H3 on serine 10, a modification previously associated with positive gene expression. Furthermore, we show that IKK-alpha can directly phosphorylate histone H3 in vitro, suggesting a new substrate for this kinase. We propose that IKK-alpha is an essential regulator of NF-kappaB-dependent gene expression through control of promoter-associated histone phosphorylation after cytokine exposure. These findings provide additional insight into the role of the IKK complex in NF-kappaB-regulated gene expression.