Partner: Paweł Nałęcz-Jawecki

University of Warsaw (PL)

Ostatnie publikacje
1.Korwek Z., Tudelska K., Nałęcz-Jawecki P., Czerkies M., Prus W., Markiewicz J., Kochańczyk M., Lipniacki T., Importins promote high-frequency NF-κB oscillations increasing information channel capacity, Biology Direct, ISSN: 1745-6150, DOI: 10.1186/s13062-016-0164-z, Vol.11, No.61, pp.1-21, 2016

Streszczenie:

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.

Słowa kluczowe:

Karyopherins, Nucleocytoplasmic transport, Negative feedback, Channel information capacity, Mathematical modelling

Afiliacje autorów:

Korwek Z.-IPPT PAN
Tudelska K.-other affiliation
Nałęcz-Jawecki P.-University of Warsaw (PL)
Czerkies M.-IPPT PAN
Prus W.-IPPT PAN
Markiewicz J.-IPPT PAN
Kochańczyk M.-IPPT PAN
Lipniacki T.-IPPT PAN
35p.
2.Nałęcz-Jawecki P., Szymańska P., Kochańczyk M., Miękisz J., Lipniacki T., Effective reaction rates for diffusion-limited reaction cycles, JOURNAL OF CHEMICAL PHYSICS, ISSN: 0021-9606, DOI: 10.1063/1.4936131, Vol.143, No.21, pp.215102-1-12, 2015

Streszczenie:

Biological signals in cells are transmitted with the use of reaction cycles, such as the phosphorylation-dephosphorylation cycle, in which substrate is modified by antagonistic enzymes. An appreciable share of such reactions takes place in crowded environments of two-dimensional structures, such as plasma membrane or intracellular membranes, and is expected to be diffusion-controlled. In this work, starting from the microscopic bimolecular reaction rate constants and using estimates of the mean first-passage time for an enzyme–substrate encounter, we derive diffusion-dependent effective macroscopic reaction rate coefficients (EMRRC) for a generic reaction cycle. Each EMRRC was found to be half of the harmonic average of the microscopic rate constant (phosphorylation c or dephosphorylation d), and the effective (crowding-dependent) motility divided by a slowly decreasing logarithmic function of the sum of the enzyme concentrations. This implies that when c and d differ, the two EMRRCs scale differently with the motility, rendering the steady-state fraction of phosphorylated substrate molecules diffusion-dependent. Analytical predictions are verified using kinetic Monte Carlo simulations on the two-dimensional triangular lattice at the single-molecule resolution. It is demonstrated that the proposed formulas estimate the steady-state concentrations and effective reaction rates for different sets of microscopic reaction rates and concentrations of reactants, including a non-trivial example where with increasing diffusivity the fraction of phosphorylated substrate molecules changes from 10% to 90%.

Słowa kluczowe:

Enzymes, Enzyme kinetics, Diffusion, Reaction rate constants, Membrane biochemistry

Afiliacje autorów:

Nałęcz-Jawecki P.-University of Warsaw (PL)
Szymańska P.-University of Warsaw (PL)
Kochańczyk M.-IPPT PAN
Miękisz J.-University of Warsaw (PL)
Lipniacki T.-IPPT PAN
35p.