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A protein turnover signaling motif controls the stimulus-sensitivity of stress response pathways.

Loriaux PM, Hoffmann A - PLoS Comput. Biol. (2013)

Bottom Line: In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR.In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF.Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NFκB, IκBα. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NFκB signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

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Effects of IκB flux on the NFκB response to stimulation.(A) The productive flux of IκB was varied between  and  times its wildtype value prior to stimulation by TNF (light gray to dark gray), and the resulting NFκB response values  and  plotted in columns 2 and 3. Representative nuclear NFκB profiles for low, moderate, wildtype, and high values of the flux multiplier are shown at right. Again, the wildtype productive flux is indicated by the dashed line in red. (B) The futile flux of IκB was varied between  and  times its wildtype value prior to stimulation by TNF and the resulting NFκB response values  and  plotted in columns 2 and 3. (C) and (D) As rows 1 and 2, above, but the response to UV stimulation is plotted instead of TNF.
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pcbi-1002932-g006: Effects of IκB flux on the NFκB response to stimulation.(A) The productive flux of IκB was varied between and times its wildtype value prior to stimulation by TNF (light gray to dark gray), and the resulting NFκB response values and plotted in columns 2 and 3. Representative nuclear NFκB profiles for low, moderate, wildtype, and high values of the flux multiplier are shown at right. Again, the wildtype productive flux is indicated by the dashed line in red. (B) The futile flux of IκB was varied between and times its wildtype value prior to stimulation by TNF and the resulting NFκB response values and plotted in columns 2 and 3. (C) and (D) As rows 1 and 2, above, but the response to UV stimulation is plotted instead of TNF.

Mentions: The results show that reducing the productive flux yields a slower, weaker response to TNF (Figure 6A). By analogy to Figure 2, this indicates that the productive flux of IκB is a positive regulator of NFκB activation. In contrast, the futile flux acts as a negative regulator of NFκB activity, though its effects on and are more modest (Figure 6B). Thus, similar to p53, the activation of NFκB is controlled by a positive and negative regulatory flux. In response to UV, a reduction in either flux delays NFκB activation, but reducing the futile flux results in a significant increase in while reducing the productive flux has almost no effect (Figure 6C and D). Conversely, while an increase in the futile flux has no effect on , an increase in the productive flux results in a significant increase. If we now define NFκB to be sensitive to TNF or UV when or are ten-fold higher than its active but pre-stimulated steady state abundance, then TNF sensitivity requires a productive flux multiplier , while UV insensitivity requires a productive flux multiplier and a futile flux multiplier . This suggests that the flux pathways of IκB may be optimized to preserve NFκB sensitivity to external inflammatory stimuli while minimizing sensitivity to internal metabolic stresses.


A protein turnover signaling motif controls the stimulus-sensitivity of stress response pathways.

Loriaux PM, Hoffmann A - PLoS Comput. Biol. (2013)

Effects of IκB flux on the NFκB response to stimulation.(A) The productive flux of IκB was varied between  and  times its wildtype value prior to stimulation by TNF (light gray to dark gray), and the resulting NFκB response values  and  plotted in columns 2 and 3. Representative nuclear NFκB profiles for low, moderate, wildtype, and high values of the flux multiplier are shown at right. Again, the wildtype productive flux is indicated by the dashed line in red. (B) The futile flux of IκB was varied between  and  times its wildtype value prior to stimulation by TNF and the resulting NFκB response values  and  plotted in columns 2 and 3. (C) and (D) As rows 1 and 2, above, but the response to UV stimulation is plotted instead of TNF.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3585401&req=5

pcbi-1002932-g006: Effects of IκB flux on the NFκB response to stimulation.(A) The productive flux of IκB was varied between and times its wildtype value prior to stimulation by TNF (light gray to dark gray), and the resulting NFκB response values and plotted in columns 2 and 3. Representative nuclear NFκB profiles for low, moderate, wildtype, and high values of the flux multiplier are shown at right. Again, the wildtype productive flux is indicated by the dashed line in red. (B) The futile flux of IκB was varied between and times its wildtype value prior to stimulation by TNF and the resulting NFκB response values and plotted in columns 2 and 3. (C) and (D) As rows 1 and 2, above, but the response to UV stimulation is plotted instead of TNF.
Mentions: The results show that reducing the productive flux yields a slower, weaker response to TNF (Figure 6A). By analogy to Figure 2, this indicates that the productive flux of IκB is a positive regulator of NFκB activation. In contrast, the futile flux acts as a negative regulator of NFκB activity, though its effects on and are more modest (Figure 6B). Thus, similar to p53, the activation of NFκB is controlled by a positive and negative regulatory flux. In response to UV, a reduction in either flux delays NFκB activation, but reducing the futile flux results in a significant increase in while reducing the productive flux has almost no effect (Figure 6C and D). Conversely, while an increase in the futile flux has no effect on , an increase in the productive flux results in a significant increase. If we now define NFκB to be sensitive to TNF or UV when or are ten-fold higher than its active but pre-stimulated steady state abundance, then TNF sensitivity requires a productive flux multiplier , while UV insensitivity requires a productive flux multiplier and a futile flux multiplier . This suggests that the flux pathways of IκB may be optimized to preserve NFκB sensitivity to external inflammatory stimuli while minimizing sensitivity to internal metabolic stresses.

Bottom Line: In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR.In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF.Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NFκB, IκBα. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NFκB signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

Show MeSH
Related in: MedlinePlus