Two-component systems are one of the primary modes of signal transduction that bacteria use to sense and respond to their environment. These circuits play a key role in enabling bacteria to adapt to diverse growth conditions, control developmental programs, and initiate pathogenic lifestyles. The prototypical two-component system consists of two-proteins, an upstream histidine kinase that is usually involved in signal detection, and a downstream response regulator, which controls the circuit output. Information flow occurs by transfer of a phosphoryl group from the histidine kinase to the response regulator. Two-component systems can deviate from this simple architecture, however, and have additional protein components or more complex phosphotransfer paths. In previous work we discovered that a small 47 amino acid membrane protein, MgrB, inhibits PhoQ activity. Since MgrB expression is activated by PhoP, the protein functions as part of a negative feedback loop in the PhoQ/PhoP circuit. PhoQ is also stimulated by SafA, another small membrane protein, whose expression is controlled by the acid-responsive EvgS/EvgA two component systems. MgrB and SafA are among a group of recently discovered small hydrophobic proteins that modulate histidine kinase function. In this proposal we will combine fluorescence microscopy to follow circuit behavior in single cells, with genetic analysis and modeling to explore the role of MgrB and SafA in PhoQ/PhoP signaling. We will determine the effect of these proteins on the dynamics and input-output behavior of PhoQ/PhoP signaling for stimulation with magnesium, antimicrobial peptides and pH, compare the behavior of the low pH response among natural E. coli isolates, characterize new input signals that modulate the PhoQ/PhoP circuit through MgrB, and study the growth defect associated with dysregulation of the MgrB-PhoQ-PhoP pathway.

Public Health Relevance

The PhoQ/PhoP regulatory circuit is a critical system for enabling bacteria such as Escherichia coli and Salmonella to colonize animal hosts and cause disease. Progress in understanding the regulation of this system by small membrane proteins, the focus of this proposal, will further our understanding of how these bacteria resist host defenses and may aid in the development of new antibiotics and compounds that specifically inhibit the virulence of these pathogens.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Maas, Stefan
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University of Pennsylvania
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Chen, Annie I; Goulian, Mark (2018) A network of regulators promotes dehydration tolerance in Escherichia coli. Environ Microbiol 20:1283-1295
Culyba, Matthew J; Kubiak, Jeffrey M; Mo, Charlie Y et al. (2018) Non-equilibrium repressor binding kinetics link DNA damage dose to transcriptional timing within the SOS gene network. PLoS Genet 14:e1007405
Friedman, Elliot S; Bittinger, Kyle; Esipova, Tatiana V et al. (2018) Microbes vs. chemistry in the origin of the anaerobic gut lumen. Proc Natl Acad Sci U S A 115:4170-4175
Schulte, Jane E; Goulian, Mark (2018) The Phosphohistidine Phosphatase SixA Targets a Phosphotransferase System. MBio 9:
Carey, Jeffrey N; Goulian, Mark (2018) A bacterial signaling system regulates noise to enable bet hedging. Curr Genet :
Carey, Jeffrey N; Mettert, Erin L; Roggiani, Manuela et al. (2018) Regulated Stochasticity in a Bacterial Signaling Network Permits Tolerance to a Rapid Environmental Change. Cell 175:1989-1990
Carey, Jeffrey N; Mettert, Erin L; Roggiani, Manuela et al. (2018) Regulated Stochasticity in a Bacterial Signaling Network Permits Tolerance to a Rapid Environmental Change. Cell 173:196-207.e14
Ni, Josephine; Shen, Ting-Chin David; Chen, Eric Z et al. (2017) A role for bacterial urease in gut dysbiosis and Crohn's disease. Sci Transl Med 9:
Jishkariani, Davit; MacDermaid, Christopher M; Timsina, Yam N et al. (2017) Self-interrupted synthesis of sterically hindered aliphatic polyamide dendrimers. Proc Natl Acad Sci U S A 114:E2275-E2284
Niepa, Tagbo H R; Vaccari, Liana; Leheny, Robert L et al. (2017) Films of Bacteria at Interfaces (FBI): Remodeling of Fluid Interfaces by Pseudomonas aeruginosa. Sci Rep 7:17864

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