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

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.

SUBMITTER: Rao SD

PROVIDER: S-EPMC7808668 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Rao Satyajit D SD Igoshin Oleg A OA

PLoS computational biology 20210104 1

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 stea ...[more]

PMID: 33395414

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Project description:BackgroundFeedback loops, both positive and negative are embedded in the Mitogen Activated Protein Kinase (MAPK) cascade. In the three layer MAPK cascade, both feedback loops originate from the terminal layer and their sites of action are either of the two upstream layers. Recent studies have shown that the cascade uses coupled positive and negative feedback loops in generating oscillations. Two plausible designs of coupled positive and negative feedback loops can be elucidated from the literature; in one design the positive feedback precedes the negative feedback in the direction of signal flow and vice-versa in another. But it remains unexplored how the two designs contribute towards triggering oscillations in MAPK cascade. Thus it is also not known how amplitude, frequency, robustness or nature (analogous/digital) of the oscillations would be shaped by these two designs.ResultsWe built two models of MAPK cascade that exhibited oscillations as function of two underlying designs of coupled positive and negative feedback loops. Frequency, amplitude and nature (digital/analogous) of oscillations were found to be differentially determined by each design. It was observed that the positive feedback emerging from an oscillating MAPK cascade and functional in an external signal processing module can trigger oscillations in the target module, provided that the target module satisfy certain parametric requirements. The augmentation of the two models was done to incorporate the nuclear-cytoplasmic shuttling of cascade components followed by induction of a nuclear phosphatase. It revealed that the fate of oscillations in the MAPK cascade is governed by the feedback designs. Oscillations were unaffected due to nuclear compartmentalization owing to one design but were completely abolished in the other case.ConclusionThe MAPK cascade can utilize two distinct designs of coupled positive and negative feedback loops to trigger oscillations. The amplitude, frequency and robustness of the oscillations in presence or absence of nuclear compartmentalization were differentially determined by two designs of coupled positive and negative feedback loops. A positive feedback from an oscillating MAPK cascade was shown to induce oscillations in an external signal processing module, uncovering a novel regulatory aspect of MAPK signal processing.

Dataset Information

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

Publications

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

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