Park Gye Young, Wang Xuerong, Hu Ningning, Pedchenko Tetyana V, Blackwell Timothy S, Christman John W
Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, Illinois 60612, USA.
J Biol Chem. 2006 Jul 7;281(27):18684-90. doi: 10.1074/jbc.M600733200. Epub 2006 May 3.
The exact physiological role of NF-kappaB-inducing kinase (NIK) in the NF-kappaB activation pathway has not been defined, although it is an upstream kinase of IKKalpha. Recent studies have indicated that IKKalpha is a nucleosomal modifier of NF-kappaB signaling. We hypothesized that NIK generates a proximal signal that contributes to IKKalpha modification of nucleosomal structure through phosphorylation of histone H3 and enhancement of target gene expression. By using a chromatin immunoprecipitation assay, our data show that endogenous IKKalpha is recruited to the promoter site of several NF-kappaB-dependent genes in macrophages. Our data show that immunoreactive NIK is rapidly recruited to nuclear compartment in macrophages in response to treatment with endotoxin where it augments phosphorylation of histone H3 by inducing phosphorylation and kinase activity of IKKalpha. A small interfering RNA knockdown of NIK markedly reduces phosphorylation of histone H3 in endotoxin treated macrophages. These data, together, demonstrate a novel role for NIK as a histone H3 modifier, through an accessory pathway from NIK to IKKalpha, that could play an important role in the endotoxin response through modification of nucleosomal structure.
核因子κB诱导激酶（NIK）在核因子κB激活途径中的确切生理作用尚未明确，尽管它是IKKα的上游激酶。最近的研究表明，IKKα是核因子κB信号传导的核小体修饰因子。我们推测，NIK产生一个近端信号，通过组蛋白H3的磷酸化和靶基因表达的增强，有助于IKKα对核小体结构的修饰。通过染色质免疫沉淀试验，我们的数据显示内源性IKKα被募集到巨噬细胞中几个核因子κB依赖性基因的启动子位点。我们的数据显示，免疫反应性NIK在巨噬细胞中被内毒素处理后迅速募集到核区室，在那里它通过诱导IKKα的磷酸化和激酶活性来增强组蛋白H3的磷酸化。NIK的小干扰RNA敲低显著降低了内毒素处理的巨噬细胞中组蛋白H3的磷酸化。这些数据共同证明了NIK作为组蛋白H3修饰因子的新作用，通过从NIK到IKKα的辅助途径，这可能通过核小体结构的修饰在内毒素反应中发挥重要作用。
