Kim Hong-Bum, Evans Iona, Smallwood Rod, Holcombe Mike, Qwarnstrom Eva E
Academic Unit of Cell Biology, School of Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom.
Biosystems. 2010 Feb;99(2):140-9. doi: 10.1016/j.biosystems.2009.10.009. Epub 2009 Nov 10.
Activation of the transcription factor NF-kappaB is central to control of immune and inflammatory responses. Cytokine induced activation through the classical or canonical pathway relies on degradation of the inhibitor, IkappaBalpha and regulation by the IKKbeta kinase. In addition, the NF-kappaB is activated through the NF-kappaB-inducing kinase, NIK. Analysis of the IKK/NIK inter-relationship and its impact on NF-kappaB control, were analysed by mathematical modelling, using matrix formalism and stoichiometrically balanced reactions. The analysis considered a range of bio-reactions and core metabolites and their role in relation to kinase activation and in control of specific steps of the NF-kappaB pathway. The model predicts a growth-rate and time-dependent transfer of the primary kinase activity from IKKbeta to NIK. In addition, it suggests that NIK/IKKbeta interdependence is controlled by intermediates of phosphoribosylpyrophosphate (PRPP) within the glycolysis pathway, and thus, identifies a link between specific metabolic events and kinase activation in inflammatory signal transduction. Subsequent in vitro experiments, carried out to validate the impact of IKK/NIK interdependence, confirmed signal amplification at the level of the NF-kappaB/IkappaBalpha complex control in the presence of both kinases. Further, they demonstrate that the induced potentiation is due to synergistic enhancement of relA-dependent activation.
转录因子NF-κB的激活是免疫和炎症反应调控的核心。细胞因子通过经典或标准途径诱导的激活依赖于抑制剂IκBα的降解以及IKKβ激酶的调控。此外，NF-κB通过NF-κB诱导激酶NIK被激活。利用矩阵形式和化学计量平衡反应，通过数学建模分析了IKK/NIK的相互关系及其对NF-κB调控的影响。该分析考虑了一系列生物反应和核心代谢物及其在激酶激活和NF-κB途径特定步骤调控中的作用。该模型预测了初级激酶活性从IKKβ到NIK的生长速率和时间依赖性转移。此外，它表明NIK/IKKβ的相互依赖性受糖酵解途径中磷酸核糖焦磷酸（PRPP）中间体的控制，因此，确定了炎症信号转导中特定代谢事件与激酶激活之间的联系。随后进行的体外实验旨在验证IKK/NIK相互依赖性的影响，证实在两种激酶存在的情况下，在NF-κB/IκBα复合物控制水平上信号放大。此外，它们证明诱导的增强作用是由于relA依赖性激活的协同增强。
