title: Identification of new IκBα complexes by an iterative experimental and mathematical modeling approach.
abstract: The transcription factor nuclear factor kappa-B (NFκB) is a key regulator of pro-inflammatory and pro-proliferative processes. Accordingly, uncontrolled NFκB activity may contribute to the development of severe diseases when the regulatory system is impaired. Since NFκB can be triggered by a huge variety of inflammatory, pro-and anti-apoptotic stimuli, its activation underlies a complex and tightly regulated signaling network that also includes multi-layered negative feedback mechanisms. Detailed understanding of this complex signaling network is mandatory to identify sensitive parameters that may serve as targets for therapeutic interventions. While many details about canonical and non-canonical NFκB activation have been investigated, less is known about cellular IκBα pools that may tune the cellular NFκB levels. IκBα has so far exclusively been described to exist in two different forms within the cell: stably bound to NFκB or, very transiently, as unbound protein. We created a detailed mathematical model to quantitatively capture and analyze the time-resolved network behavior. By iterative refinement with numerous biological experiments, we yielded a highly identifiable model with superior predictive power which led to the hypothesis of an NFκB-lacking IκBα complex that contains stabilizing IKK subunits. We provide evidence that other but canonical pathways exist that may affect the cellular IκBα status. This additional IκBα:IKKγ complex revealed may serve as storage for the inhibitor to antagonize undesired NFκB activation under physiological and pathophysiological conditions.
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany; Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Konrath
authors.affiliation: Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Witt
authors.affiliation: Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sauter
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany; Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kulms
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001671:Biochemistry / Q000379:methods*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008962:Models, Theoretical; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D014638:Vanadates / Q000737:chemistry
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D014638:Vanadates