IκBε provides negative feedback to control NF-κB oscillations, signaling dynamics, and inflammatory gene expression

Abstract

NF-κB signaling is known to be critically regulated by the NF-κB–inducible inhibitor protein IκBα. The resulting negative feedback has been shown to produce a propensity for oscillations in NF-κB activity. We report integrated experimental and computational studies that demonstrate that another IκB isoform, IκBɛ, also provides negative feedback on NF-κB activity, but with distinct functional consequences. Upon stimulation, NF-κB–induced transcription of IκBɛ is delayed, relative to that of IκBα, rendering the two negative feedback loops to be in antiphase. As a result, IκBɛ has a role in dampening IκBα-mediated oscillations during long-lasting NF-κB activity. Furthermore, we demonstrate the requirement of both of these distinct negative feedback regulators for the termination of NF-κB activity and NF-κB–mediated gene expression in response to transient stimulation. Our findings extend the capabilities of a computational model of IκB–NF-κB signaling and reveal a novel regulatory module of two antiphase negative feedback loops that allows for the fine-tuning of the dynamics of a mammalian signaling pathway.

Kinetic control of negative feedback regulators of NF-κB/RelA determines their pathogen- and cytokine-receptor signaling specificity

“…With I B␣ being thought of as the primary negative feedback regulator, I B was found to provide for a ''fail-safe'' mechanism in resting or transiently stimulated cells (5,6). The highly inducible de-ubiquitinase A20, which functions upstream of IKK, was found to function primarily as a rheostat that mediates signaling cross-talk rather than an obligate negative feedback regulator (16).…”

Crosstalk via the NF-κB signaling system

“…A detailed understanding of these biochemical events has allowed for the construction of a mathematical model that recapitulates the experimentally observed NF-κB activation dynamics during the TNF response (Hoffmann et al, 2002;Kearns et al, 2006). This mathematical model provided an in silico confirmation that the known biochemical mechanisms, such as stimulus-responsive degradation and resynthesis of IκBs, its association/dissociation with the RelA:p50 dimer, nuclear import and export of free and IκB-bound RelA:p50 dimers, are sufficient to explain the observed NF-κB regulation in response to the canonical pathway activation (Fig.…”

A single NFκB system for both canonical and non-canonical signaling

“…IκBα deficiency for example, which alters the TNF-induced dynamic controls, results in inappropriate gene expression [48]. Further, IκBε appears to dampen IκBα-mediated NFκB oscillations, because its mRNA induction is delayed to occur in anti-phase with that of IκBα [49]. In addition, newly synthesized IκBδ forms a negative feedback loop to regulate RelA:p50 activity in a stimulus-specific manner, as described above [3].…”