title: Anatomy of a negative feedback loop: the case of IκBα.
abstract: The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an 'activator-induced inhibitor' regulatory motif. Within the NFκB signalling pathway, a key negative feedback regulator is IκBα. We show here that, contrary to current understanding, NFκB-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NFκB signalling to identify IκBα molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of IκBα and the IκBα-NFκB complex, as well as the free IκBα half-life, as key determinants of post-induction repression of NFκB and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required 'activator-induced inhibitor' relationship.
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Riku
authors: R
authors: Fagerlund
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Marcelo
authors: M
authors: Behar
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Karen T
authors: KT
authors: Fortmann
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095, USA.
authors: Y Eason
authors: YE
authors: Lin
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095, USA.
authors: Jesse D
authors: JD
authors: Vargas
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095, USA ahoffmann@ucla.edu.
authors: Alexander
authors: A
authors: Hoffmann
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D003198:Computer Simulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016328:NF-kappa B; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase
keywords: IκBα; NFκB; gene regulation; negative feedback; oscillation