Interleukin-1 receptor-associated kinase (IRAK)-1-mediated NF-κB activation requires cytosolic and nuclear activity
Interleukin-1 receptor-associated kinase (IRAK)-1-mediated NF-κB activation requires cytosolic and nuclear activity
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DOI：
10.1096/fj.07-101816
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Abraham, Edward
中科院分区：
文献类型：
--
作者：
Liu, Gang;Park, Young-Jun;Abraham, Edward
白细胞介素-1受体相关激酶（IRAK）-1通过参与IKK激活在Toll样受体/白细胞介素-1受体（TLR/IL-1 R）相关的NF-κ B激活中起重要作用，随后导致I κ B降解和NF-κ B核转位。在目前的研究中，我们证明了一种新的途径，其中IRAK-1存在于细胞核中参与NF-κ B依赖的基因表达。IRAK-1的核定位在用IL-1和LPS或CRM-1依赖性核输出阻断的细胞刺激下增加。IRAK-1的诱导产生增强的NF-κ B转录活性，其先于I κ B-α降解和NF-κ B的核转位。IRAK-1与NF-κ B调节基因I κ B-α的启动子结合，并增强NF-κ B B p65亚基与I κ B-α启动子内的NF-κ B应答元件的结合。IRAK-1在体外磷酸化组蛋白H3，并且是体内IL-1诱导的组蛋白H3在丝氨酸10处磷酸化所必需的。这些数据表明IRAK-1的胞质和核作用都参与NF κ B依赖性转录事件的激活。
Interleukin-1 receptor-associated kinase (IRAK) -1 plays an essential role in Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) -associated NF-kappa B activation through its involvement in IKK activation, which then leads to subsequent I kappa B degradation and NF-kappa B nuclear translocation. In the present studies, we demonstrate a novel pathway in which IRAK-1 present in the nucleus participates in NF-kappa B-dependent gene expression. Nuclear localization of IRAK-1 is increased on cellular stimulation with IL-1 and LPS, or CRM-1-dependent nuclear export blockade. Induction of IRAK-1 produces enhanced NF-kappa B transcriptional activity that precedes I kappa B-alpha degradation and nuclear translocation of NF-kappa B. IRAK-1 binds to the promoter of NF-kappa B-regulated gene, I kappa B-alpha, and enhances binding of the NF-kappa B p65 subunit to NF-kappa B responsive elements within the I kappa B-alpha promoter. IRAK-1 phosphorylates histone H3 in vitro and is required for IL-1-induced phosphorylation of histone H3 at serine 10 in vivo. These data indicate that both cytosolic and nuclear actions of IRAK-1 participate in the activation of NF kappa B-dependent transcriptional events.