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O'Dea et al. (2007), IκB Metabolism

February 2008, model of the month by Dominic P. Tolle
Original model: BIOMD0000000147

NF-κB is one of the main transcription factors activated during the inflammatory response. In absence of an induction signal, NF-κB is present within the cytosol in an inactive form, bound to an inhibitor protein, IκB. IκB sequesters NF-κB and prevents it from activating its downstream targets by concealing the nuclear localisation sequence of NF-κB and inhibiting its DNA-binding activity. An inflammation signal leads to NF-κB activity by removing the inhibitor. The induction signal works through activating the serine/threonine kinase IκB kinase (IKK). IKK catalyses the phosphorylation of IκB which leads to subsequent ubiquitylation and degradation of IκB. Once freed of its inhibitor, NF-κB translocates to the nucleus to act as transcription factor for a large host of genes. Although much is known about the behaviour of the NF-κB module following an induction event, the mechanisms controlling IκB turnover in the absence of an induction signal remain poorly understood.

In this model of the month (BIOMD0000000147), a model of IκB turnover (see figure 1) created by O'Dea et al. is described [1]. Although previous models have been created which accurately model the response of NF-κB to the induction stimulus [2], these models contradict experimental results in regard to IκB levels in the unstimulated state. O'Dea et al. model IκB degradation using four separate degradation reactions, taking into account IκB in its bound and unbound form, as well as the induced, IKK-dependent and constitutive IKK-independent pathway (see figure 1B). The authors altered one of the four rate constants with a multiplier ranging from 0.01 to 100, and then performed simulations of TNF signalling on the system. The average nuclear NF-κB levels during early phase and the later attenuation phase (see figure 1C) of the TNF response were plotted.

Changes in the IKK-dependent degradation rate of bound IκB affect the nuclear levels of NF-κB both during the first hour of TNF stimulation, as well as during the attenuation phase (see figure 1D&E, red lines), whereas the model predicts NF-κB levels to be insensitive to changes in the IKK-dependent degradation of free IκB (see figure 1D&E, blue lines). In contrast, the IKK-independent degradation rate of free IκB appears much more sensitive to changes in parameter values during both the early phase and the late phase, compared to the IKK-independent degradation rate of bound IκB (see figure 1F&G, blue lines and red lines respectively).

NF-κB is present in the majority of cells found in the human body. It is of great importance during processes such as development and inflammation, and it's activity requires strict regulation. The above model describes NF-κB regulation during the early phases following TNF stimulation, as well as during the late attenuation phase of the response. It highlights the importance of the numerous degradation pathways controlling NF-κB activity during the various phases. Computational models quite often can bring aspects of systems to the attention of researchers, which otherwise may have received little attention. As such, the model acts as the vanguard for laboratory experiments. In the model above, the control of NF-κB activity involving the IKK-independent degradation especially has prompted the authors to further investigate this process in the laboratory.

degradation pathways of IkappaB

Figure 1: The degradation pathways of IκB and the parameter sensitivity of the pathways. From [1].

Bibliographic References

  1. E. L. O'Dea, D. Barken, R. Q. Peralta, K. T. Tran, S. L. Werner, J. D. Kearns, A. Levchenko, A. Hoffmann. A homeostatic model of IkappaB metabolism to control constitutive NF-kappaB activity. Mol Sys Biol, 3:111, 2007. [SRS@EBI]
  2. T. Lipniacki, P. Paszek, A. R. Brasier, B. Luxon, M. Kimmel. Mathematical model of NF-kappaB regulatory module. J Theor Biol, 288:195-215, 2004. [SRS@EBI]