A computational approach to investigate constitutive activation of NF-κB.

ABSTRACT

Nuclear factor kappa B (NF-κB) signaling is the master regulator of inflammatory pathways; therefore, its regulation has been the subject of investigation since last two decades. Multiple models have been published that describes the dynamics of NF-κB activity by stimulated activation and feedback loops. However, there is also paramount evidence of the critical role of posttranslational modifications (PTMs) in the regulation of NF-κB pathway. With the premise that PTMs present alternate routes for activation or repression of the NF-κB pathway, we have developed a model including all PTMs known so far describing the system behavior. We present a pathway network model consisting of 171 proteins forming 315 molecular species and consisting of 482 reactions that describe the NF-κB activity regulation in totality. The overexpression or knockdown of interacting molecular partners that regulate NF-κB transcriptional activity by PTMs is used to infer the dynamics of NF-κB activity and offers qualitative agreement between model predictions and the experimental results heuristically. Finally, we have demonstrated an instance of NF-κB constitutive activation through positive upregulation of cytokines (the stimuli) and IKK complex (NF-κB activator), the characteristic features in several cancer types and metabolic disorders, and its reversal by employing combinatorial activation of PPARG, PIAS3, and P50-homodimer. For the first time, we have presented a NF-κB model that includes transcriptional regulation by PTMs and presented a theoretical strategy for the reversal of NF-κB constitutive activation. The presented model would be important in understanding the NF-κB system, and the described method can be used for other pathways as well.