Abstract
The transcription factor nuclear factor kappa-B (NF$\kappa$B) is a key regulator of pro-inflammatory and pro-proliferative processes. Accordingly, uncontrolled NF$\kappa$B activity may contribute to the development of severe diseases when the regulatory system is impaired. Since NF$\kappa$B can be triggered by a huge variety of inflammatory, pro-and anti-apoptotic stimuli, its activation underlies a complex and tightly regulated signaling network that also includes multi-layered negative feedback mechanisms. Detailed understanding of this complex signaling network is mandatory to identify sensitive parameters that may serve as targets for therapeutic interventions. While many details about canonical and non-canonical NF$\kappa$B activation have been investigated, less is known about cellular I$\kappa$B$\alpha$ pools that may tune the cellular NF$\kappa$B levels. I$\kappa$B$\alpha$ has so far exclusively been described to exist in two different forms within the cell: stably bound to NF$\kappa$B or, very transiently, as unbound protein. We created a detailed mathematical model to quantitatively capture and analyze the time-resolved network behavior. By iterative refinement with numerous biological experiments, we yielded a highly identifiable model with superior predictive power which led to the hypothesis of an NF$\kappa$B-lacking I$\kappa$B$\alpha$ complex that contains stabilizing IKK subunits. We provide evidence that other but canonical pathways exist that may affect the cellular I$\kappa$B$\alpha$ status. This additional I$\kappa$B$\alpha$:IKK$\gamma$ complex revealed may serve as storage for the inhibitor to antagonize undesired NF$\kappa$B activation under physiological and pathophysiological conditions.
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