1. Importins promote high-frequency NF-κB oscillations increasing information channel capacity
- Author
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Zbigniew Korwek, Karolina Tudelska, Joanna Markiewicz, Tomasz Lipniacki, Maciej Czerkies, Wiktor Prus, Paweł Nałęcz-Jawecki, and Marek Kochańczyk
- Subjects
0301 basic medicine ,Immunology ,Importin ,Karyopherins ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Negative feedback ,Animals ,Nuclear pore ,Transcription factor ,Cells, Cultured ,Ecology, Evolution, Behavior and Systematics ,Nucleocytoplasmic transport ,Agricultural and Biological Sciences(all) ,Mathematical modelling ,Biochemistry, Genetics and Molecular Biology(all) ,Research ,Channel information capacity ,Applied Mathematics ,NF-kappa B p50 Subunit ,NF-κB ,Fibroblasts ,Immunity, Innate ,Cell biology ,IκBα ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,030220 oncology & carcinogenesis ,Modeling and Simulation ,Regulatory Pathway ,General Agricultural and Biological Sciences ,Nuclear localization sequence ,Signal Transduction - Abstract
Background Importins and exportins influence gene expression by enabling nucleocytoplasmic shuttling of transcription factors. A key transcription factor of innate immunity, NF-κB, is sequestered in the cytoplasm by its inhibitor, IκBα, which masks nuclear localization sequence of NF-κB. In response to TNFα or LPS, IκBα is degraded, which allows importins to bind NF-κB and shepherd it across nuclear pores. NF-κB nuclear activity is terminated when newly synthesized IκBα enters the nucleus, binds NF-κB and exportin which directs the complex to the cytoplasm. Although importins/exportins are known to regulate spatiotemporal kinetics of NF-κB and other transcription factors governing innate immunity, the mechanistic details of these interactions have not been elucidated and mathematically modelled. Results Based on our quantitative experimental data, we pursue NF-κB system modelling by explicitly including NF-κB–importin and IκBα–exportin binding to show that the competition between importins and IκBα enables NF-κB nuclear translocation despite high levels of IκBα. These interactions reduce the effective relaxation time and allow the NF-κB regulatory pathway to respond to recurrent TNFα pulses of 45-min period, which is about twice shorter than the characteristic period of NF-κB oscillations. By stochastic simulations of model dynamics we demonstrate that randomly appearing, short TNFα pulses can be converted to essentially digital pulses of NF-κB activity, provided that intervals between input pulses are not shorter than 1 h. Conclusions By including interactions involving importin-α and exportin we bring the modelling of spatiotemporal kinetics of transcription factors to a more mechanistic level. Basing on the analysis of the pursued model we estimated the information transmission rate of the NF-κB pathway as 1 bit per hour. Reviewers This article was reviewed by Marek Kimmel, James Faeder and William Hlavacek. Electronic supplementary material The online version of this article (doi:10.1186/s13062-016-0164-z) contains supplementary material.
- Published
- 2016