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

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.