A homeostatic model of IκB metabolism to control constitutive NF-κB activity

Cellular signal transduction pathways are usually studied following administration of an external stimulus. However, disease-associated aberrant activity of the pathway is often due to misregulation of the equilibrium state. The transcription factor NF-κB is typically described as being held inactive in the cytoplasm by binding its inhibitor, IκB, until an external stimulus triggers IκB degradation through an IκB kinase-dependent degradation pathway. Combining genetic, biochemical, and computational tools, we investigate steady-state regulation of the NF-κB signaling module and its impact on stimulus responsiveness. We present newly measured in vivo degradation rate constants for NF-κB-bound and -unbound IκB proteins that are critical for accurate computational predictions of steady-state IκB protein levels and basal NF-κB activity. Simulations reveal a homeostatic NF-κB signaling module in which differential degradation rates of free and bound pools of IκB represent a novel cross-regulation mechanism that imparts functional robustness to the signaling module.