Importins promote high-frequency NF-κB oscillations increasing information channel capacity.
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.



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.



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.



This article was reviewed by Marek Kimmel, James Faeder and William Hlavacek.
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Zbigniew
Z
Korwek
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Karolina
K
Tudelska
College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.
Paweł
P
Nałęcz-Jawecki
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Maciej
M
Czerkies
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Wiktor
W
Prus
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Joanna
J
Markiewicz
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Marek
M
Kochańczyk
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland. tlipnia@ippt.pan.pl.
Tomasz
0000-0002-3488-2561
T
Lipniacki
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics*; D028884:Karyopherins / Q000737:chemistry*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000737:chemistry*; D015398:Signal Transduction
D028884:Karyopherins; D052002:NF-kappa B p50 Subunit; C073701:Nfkb1 protein, mouse
Channel information capacity; Karyopherins; Mathematical modelling; Negative feedback; Nucleocytoplasmic transport