Article,
NIK and IKK interdependence in NF-B signalling - Flux analysis of regulation through metabolites
Biosystems, (Nov 10, 2009)
DOI: 10.1016/j.biosystems.2009.10.009
Abstract
Activation of the transcription factor NF-κB is central to control of immune and inflammatory responses. Cytokine induced activation through the classical or canonical pathway relies on degradation of the inhibitor, IκBα and regulation by the IKKβ kinase. In addition, the NF-κB is activated through the NF-κB-inducing kinase, NIK. Analysis of the IKK/NIK inter-relationship and its impact on NF-κB 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-κB pathway. The model predicts a growth-rate and time dependent transfer of the primary kinase activity from IKKβ to NIK. In addition, it suggests that NIK/IKKβ 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-κB/IκBα complex control in the presence of both kinases. Further, they demonstrate that the induced potentiation is due to synergistic enhancement of relA-dependent activation.
