Overlaid positive and negative feedback loops shape dynamical properties of PhoPQ two-component system

PLoS Comput Biol. 2021 Jan 4;17(1):e1008130. doi: 10.1371/journal.pcbi.1008130. eCollection 2021 Jan.

Abstract

Bacteria use two-component systems (TCSs) to sense environmental conditions and change gene expression in response to those conditions. To amplify cellular responses, many bacterial TCSs are under positive feedback control, i.e. increase their expression when activated. Escherichia coli Mg2+ -sensing TCS, PhoPQ, in addition to the positive feedback, includes a negative feedback loop via the upregulation of the MgrB protein that inhibits PhoQ. How the interplay of these feedback loops shapes steady-state and dynamical responses of PhoPQ TCS to change in Mg2+ remains poorly understood. In particular, how the presence of MgrB feedback affects the robustness of PhoPQ response to overexpression of TCS is unclear. It is also unclear why the steady-state response to decreasing Mg2+ is biphasic, i.e. plateaus over a range of Mg2+ concentrations, and then increases again at growth-limiting Mg2+. In this study, we use mathematical modeling to identify potential mechanisms behind these experimentally observed dynamical properties. The results make experimentally testable predictions for the regime with response robustness and propose a novel explanation of biphasic response constraining the mechanisms for modulation of PhoQ activity by Mg2+ and MgrB. Finally, we show how the interplay of positive and negative feedback loops affects the network's steady-state sensitivity and response dynamics. In the absence of MgrB feedback, the model predicts oscillations thereby suggesting a general mechanism of oscillatory or pulsatile dynamics in autoregulated TCSs. These results improve the understanding of TCS signaling and other networks with overlaid positive and negative feedback.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Escherichia coli Proteins
  • Membrane Proteins
  • MgrB protein, E coli
  • PhoP protein, E coli
  • PhoQ protein, E coli
  • Magnesium

Grants and funding

The research was supported by Welch Foundation Grant C-1995, National Science Foundation grant MCB-1616755 to OAI and is NSF PHY 201974 award for the Center of Theoretical Biological Physics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.