A nucleosomal function for I kappa B kinase-alpha in NF-kappa B-dependent gene expression

Article

关键词: HISTONE H3;    NEMO/IKK-GAMMA;    IKK-ALPHA;    PHOSPHORYLATION;    ACETYLATION;    INDUCTION;    ACTIVATION;    PATHWAY;    BETA;   

DOI  :  10.1038/nature01648

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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