High stimulus unmasks positive feedback in an autoregulated bacterial signaling circuit

Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17457-62. doi: 10.1073/pnas.0807278105. Epub 2008 Nov 5.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacterial Proteins / metabolism*
  • Escherichia coli / physiology*
  • Escherichia coli Proteins / metabolism*
  • Feedback, Physiological / genetics
  • Feedback, Physiological / physiology*
  • Fluorescence
  • Gene Expression Regulation, Bacterial / genetics
  • Gene Expression Regulation, Bacterial / physiology*
  • Magnesium
  • Models, Biological*
  • Phosphorylation
  • Signal Transduction / genetics
  • Signal Transduction / physiology*

Substances

  • Bacterial Proteins
  • Escherichia coli Proteins
  • PhoP protein, E coli
  • PhoQ protein, Bacteria
  • Magnesium