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

Biol Direct. 2016 Nov 11;11(1):61. doi: 10.1186/s13062-016-0164-z.


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.

Keywords: Channel information capacity; Karyopherins; Mathematical modelling; Negative feedback; Nucleocytoplasmic transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Fibroblasts
  • Gene Expression Regulation
  • Immunity, Innate / genetics*
  • Karyopherins / chemistry*
  • Mice
  • NF-kappa B p50 Subunit / chemistry*
  • Signal Transduction*


  • Karyopherins
  • NF-kappa B p50 Subunit
  • Nfkb1 protein, mouse