Format

Send to

Choose Destination
PLoS Comput Biol. 2014 Mar 27;10(3):e1003528. doi: 10.1371/journal.pcbi.1003528. eCollection 2014 Mar.

Identification of new IκBα complexes by an iterative experimental and mathematical modeling approach.

Author information

1
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany; Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
2
Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany.
3
Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg.
4
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany; Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, Germany.

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.

PMID:
24675998
PMCID:
PMC3967930
DOI:
10.1371/journal.pcbi.1003528
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center