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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080279-07
Application #
8656358
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Gaillard, Shawn R
Project Start
2007-06-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Kubiak, Jeffrey M; Culyba, Matthew J; Liu, Monica Yun et al. (2017) A Small-Molecule Inducible Synthetic Circuit for Control of the SOS Gene Network without DNA Damage. ACS Synth Biol 6:2067-2076
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
Yadavalli, Srujana S; Carey, Jeffrey N; Leibman, Rachel S et al. (2016) Antimicrobial peptides trigger a division block in Escherichia coli through stimulation of a signalling system. Nat Commun 7:12340
Liu, Zhi; Wang, Hui; Zhou, Zhigang et al. (2016) Differential Thiol-Based Switches Jump-Start Vibrio cholerae Pathogenesis. Cell Rep 14:347-54
Xiao, Qi; Yadavalli, Srujana S; Zhang, Shaodong et al. (2016) Bioactive cell-like hybrids coassembled from (glyco)dendrimersomes with bacterial membranes. Proc Natl Acad Sci U S A 113:E1134-41
Roggiani, Manuela; Goulian, Mark (2015) Oxygen-Dependent Cell-to-Cell Variability in the Output of the Escherichia coli Tor Phosphorelay. J Bacteriol 197:1976-87
Bhate, Manasi P; Molnar, Kathleen S; Goulian, Mark et al. (2015) Signal transduction in histidine kinases: insights from new structures. Structure 23:981-94
Patteson, A E; Gopinath, A; Goulian, M et al. (2015) Running and tumbling with E. coli in polymeric solutions. Sci Rep 5:15761
Roggiani, Manuela; Goulian, Mark (2015) Chromosome-Membrane Interactions in Bacteria. Annu Rev Genet 49:115-29

Showing the most recent 10 out of 33 publications