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.

LuxT is a Global Regulator of Low-Cell Density Behaviors Including Type III Secretion, Siderophore Production, and Aerolysin Production inVibrio harveyi

“…Two feedback loops exist in the V. harveyi LuxT/SwrZ regulatory pathway: LuxT and SwrZ activate and repress, respectively, their own transcription. Generally, positive feedback is thought to amplify responses to a stimuli, whereas negative feedback buffers pathway output against fluctuations in stimuli (45, 46). Thus, including both positive and negative feedback in a single system can alter both input sensitivity and output dynamics (46, 47).…”

“…Generally, positive feedback is thought to amplify responses to a stimuli, whereas negative feedback buffers pathway output against fluctuations in stimuli (45, 46). Thus, including both positive and negative feedback in a single system can alter both input sensitivity and output dynamics (46, 47). We speculate that the LuxT positive feedback loop enables V. harveyi to rapidly commit to the LuxT “ON” state following initial activation of luxT expression.…”

Insights into Emergence of Antibiotic Resistance in Acid-Adapted Enterohaemorrhagic Escherichia coli

“…This system comprises a complex network of two-component regulators with a wide array of interactions to cope with mild to extreme acid stress. The key interacting regulators of this network are GadE, EvgAS, PhoPQ, YdeO, GadW, RcsB, and GadX, which regulate gene expression spatially and temporally ( Figure 2 ) [ 44 , 67 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. This system is activated either by mild acidic pH during the exponential growth phase or by entry into stationary phase.…”

“…Due to this interaction, the level of RpoS increases and subsequently recruits RNA polymerase (RNAP) to RpoS-regulated promoters, including the gadE promoter [ 114 , 115 ]. Mg 2+ stress concurrently activates PhoPQ and other regulatory proteins, thereby enhancing pathogenesis by increasing pathogen survival [ 94 ].…”

“…Other studies confirm an acid-induced YadK adhesin that allows EHEC to adhere strongly to epithelial cells and facilitate bacterial-host attachment, resulting in increased colonization and pathogenesis [ 192 ]. Multiple studies with EHEC O157:H7 and other serotypes have also reported the importance of acid-induced development of other phenotypes that enhance survival and improve virulence [ 44 , 87 , 90 , 91 , 94 , 129 , 132 , 185 , 188 , 193 , 194 ]. EHECs use low pH stress to adapt and regulate a wide array of genes that enhance survival and increase pathogenicity.…”