Distinct functions of negative regulators of NF-kappaB

Abstract

The Nuclear Factor kappaB (NF-$$kappa$$B) signaling pathway is central to cellular responses to a diverse set of stimuli and stresses. It has been shown that much of this pleiotropic capacity is encoded within the activation dynamics of the upstream I$$kappa$$B Kinase (IKK), which acts as a central hub for NF-$$kappa$$B signaling. To account for how regulatory mechanisms impart specific NF- $$kappa$$B dynamics in response to IKK activity, I utilized a multidisciplinary approach that integrated mechanistic mathematical modeling with laboratory experimentation. Herein, I describe four pair wise comparisons between NF- $$kappa$$B inducible IκBα protein, the predominant regulatory mechanism, with others mediated by I$$kappa$$B$$beta$$, I$$kappa$$B$$epsilon$$, I$$kappa$$B$$delta$$ and A20. I$$kappa$$B$$epsilon$$and A20 are shown to primarily regulate the second phase of TNF responsive NF-$$kappa$$B activity by dampening oscillatory behavior and tuning the amplitude, respectively. Differences in inducible synthesis and stimulus-responsive degradation kinetics are determined to impart specific functionalities for I$$kappa$$B$$alpha$$ and I$$kappa$$B$$delta$$ negative feedback in acute/inflammatory versus chronic/pathogenic NF-$$kappa$$B signaling. In the final study, the role of I$$kappa$$B$$beta$$, a constitutive regulator, is delineated as mediating the distribution of RelA/NF-$$kappa$$B dimers in the resting cell but not their dynamics following cellular stimulation. These studies reveal the individual role of each mechanism, and collectively, the sources and functionalities of the emergent systems properties observed in cells in which these regulators act combinatorially