I[kappa]B[epsilon] provides negative feedback to control NF-[kappa]B oscillations, signaling dynamics, and inflammatory gene expression

• Published in: The Journal of cell biology 2006-06, Vol.173 (5), p.659
• Main Authors: Kearns, Jeffrey D, Basak, Soumen, Werner, Shannon L, Huang, Christine S, Hoffmann, Alexander
• Format: Article
• Language: English
• Subjects: Cellular biology; Gene expression; Genes; Proteins
• ISSN: 0021-9525; 1540-8140

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, IκBε, also provides negative feedback on NF-κB activity, but with distinct functional consequences. Upon stimulation, NF-κB-induced transcription of IκBε is delayed, relative to that of IκBα, rendering the two negative feedback loops to be in antiphase. As a result, IκBε 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. [PUBLICATION ABSTRACT]