NIK and IKK beta interdependence in NF-[kappa]B signalling - Flux analysis of regulation through metabolites

Activation of the transcription factor NF-[kappa]B is central to control of immune and inflammatory responses. Cytokine induced activation through the classical or canonical pathway relies on degradation of the inhibitor, I[kappa]B alpha and regulation by the IKK beta kinase. In addition, the NF-[kappa]B is activated through the NF-[kappa]B-inducing kinase, NIK. Analysis of the IKK/NIK inter-relationship and its impact on NF-[kappa]B 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-[kappa]B pathway. The model predicts a growth-rate and time-dependent transfer of the primary kinase activity from IKK beta to NIK. In addition, it suggests that NIK/IKK beta 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-[kappa]B/I[kappa]B alpha complex control in the presence of both kinases. Further, they demonstrate that the induced potentiation is due to synergistic enhancement of relA-dependent activation.