IkappaBepsilon provides negative feedback to control NF-kappaB oscillations, signaling dynamics, and inflammatory gene expression.
NF-kappaB signaling is known to be critically regulated by the NF-kappaB-inducible inhibitor protein IkappaBalpha. The resulting negative feedback has been shown to produce a propensity for oscillations in NF-kappaB activity. We report integrated experimental and computational studies that demonstrate that another IkappaB isoform, IkappaBepsilon, also provides negative feedback on NF-kappaB activity, but with distinct functional consequences. Upon stimulation, NF-kappaB-induced transcription of IkappaBepsilon is delayed, relative to that of IkappaBalpha, rendering the two negative feedback loops to be in antiphase. As a result, IkappaBepsilon has a role in dampening IkappaBalpha-mediated oscillations during long-lasting NF-kappaB activity. Furthermore, we demonstrate the requirement of both of these distinct negative feedback regulators for the termination of NF-kappaB activity and NF-kappaB-mediated gene expression in response to transient stimulation. Our findings extend the capabilities of a computational model of IkappaB-NF-kappaB 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.
Kearns
Jeffrey D
JD
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Basak
Soumen
S
Werner
Shannon L
SL
Huang
Christine S
CS
Hoffmann
Alexander
A
D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics*; D051379:Mice; D016328:NF-kappa B / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020672:I-kappa B Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha