High stimulus unmasks positive feedback in an autoregulated bacterial signaling circuit.
We examined the effect of positive autoregulation on the steady-state behavior of the PhoQ/PhoP two-component signaling system in Escherichia coli. We found that autoregulation has no effect on the steady-state output for a large range of input stimulus, which was modulated by varying the concentration of magnesium in the growth medium. We provide an explanation for this finding with a simple model of the PhoQ/PhoP circuit. The model predicts that even when autoregulation is manifest across a range of stimulus levels, the effects of positive feedback on the steady-state output emerge only in the limit that the system is strongly stimulated. Consistent with this prediction, amplification associated with autoregulation was observed in growth-limiting levels of magnesium, a condition that strongly activates PhoQ/PhoP. In a further test of the model, we found that strains harboring a phosphatase-defective PhoQ showed strong positive feedback and considerable cell-to-cell variability under growth conditions where the wild-type circuit did not show this behavior. Our results demonstrate a simple and general mechanism for regulating the positive feedback associated with autoregulation within a bacterial signaling circuit to boost response range and maintain a relatively uniform and graded output.
Miyashiro
Tim
T
Departments of Biology and Physics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Goulian
Mark
M
D001426:Bacterial Proteins / Q000378:metabolism*; D004926:Escherichia coli / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D025461:Feedback, Physiological / Q000235:genetics / Q000502:physiology*; D005453:Fluorescence; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics / Q000502:physiology*; D008274:Magnesium; D008954:Models, Biological; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; C465562:PhoP protein, E coli; C079792:PhoQ protein, Bacteria; D008274:Magnesium