A Protein Turnover Signaling Motif Controls the Stimulus-Sensitivity of Stress Response Pathways

Figure 5

A model of IκB-regulated NFκB activation.

(A) An IκB-centric diagram of NFκB regulation. IκB is transcribed in an NFκB-dependent and -independent manner. Translated IκB may bind to IKK (cyan), NFκB (yellow), or both (green), or it may shuttle to the nucleus and bind to NFκB there. Degradation of IκB is possible from any state, though only when bound to IKK can degradation be enhanced by IKK activity. Activation of NFκB is achieved by the time-dependent numerical inputs (magenta) and (violet). represents the activity of IKK kinase while is the efficiency of mRNA translation. Both are defined over the interval , with and being their wildtype, unstimulated values. (B) The futile (red) and productive (blue) IκB degradation fluxes. The fraction of total IκB flux through each reaction is listed next to the corresponding reaction arrow. (C) Two stimuli used in our analysis of NFκB activation and the effects of IκB flux. Stimulation by TNF is modeled using the time-dependent IKK activation profile described in [29] and results in strong but transient activation of NFκB. Stimulation by UV is modeled as a 50% reduction of translational efficiency, as described in [13], and results in modest but sustained activation. As with p53, we define and to be the maximum activity of NFκB in response to TNF and UV, respectfully, and to be the time at which is observed. Because is observed infinitely often, we define to be the time at which NFκB activation reaches one-half .

doi: https://doi.org/10.1371/journal.pcbi.1002932.g005