Perturbation of the Oxidizing Environment of the Periplasm Stimulates the PhoQ/PhoP System in Escherichia coli

Lippa, Andrew M.; Goulian, Mark

doi:10.1128/jb.06055-11

Cited by 48 publications

(57 citation statements)

References 26 publications

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“…The PhoQ protein responds to a mildly acidic pH (13, 17), low Mg 2+ (18), certain antimicrobial peptides (19), unsaturated long chain fatty acids (64), acetate concentrations (65), and the redox state in the periplasmic space (66). Which of these signals activates PhoQ during Salmonella infection of its mammalian hosts?…”

Section: Discussionmentioning

confidence: 99%

Activation of master virulence regulator PhoP in acidic pH requires the Salmonella -specific protein UgtL

Choi

Groisman

2017

Sci. Signal.

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The ability to respond to changes in pH is critical for all organisms. In Salmonella enterica, the sensor PhoQ responds to a mildly acidic pH by phosphorylating, and thereby activating, the virulence regulator PhoP. This PhoP/PhoQ two-component system is conserved in a subset of Gram-negative bacteria. PhoQ has been thought to be sufficient to activate PhoP in mildly acidic pH. However, we found that the Salmonella-specific protein UgtL, which was horizontally acquired by Salmonella before the divergence of S. enterica and S. bongori, was also necessary for PhoQ to activate PhoP under mildly acidic pH conditions, but not for PhoQ to activate PhoP in response to low Mg2+ or the antimicrobial peptide C18G. UgtL increased the abundance of phosphorylated PhoP by stimulating autophosphorylation of PhoQ, thereby increasing the amount of the phosphodonor for PhoP. Deletion of ugtL attenuated Salmonella virulence and further reduced PhoP activation in a strain bearing a form of PhoQ that is not responsive to acidic pH. Thus, when Salmonella experiences mildly acidic pH, PhoP activation requires PhoQ to detect pH and UgtL to amplify the PhoQ response. Our findings reveal how acquisition of a foreign gene can strengthen signal responsiveness in an ancestral regulatory system.

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Section: Discussionmentioning

confidence: 99%

Activation of master virulence regulator PhoP in acidic pH requires the Salmonella -specific protein UgtL

Choi

Groisman

2017

Sci. Signal.

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“…Interestingly, this effect appears to be mediated by MgrB and can be mimicked by the addition of the reducing agent DTT to the culture media (48). To test whether DsbA could affect expression of steA in S. enterica, we used an S. enterica dsbA-null mutant to measure the expression of steA::lacZ in a dsbA background.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with these previous results, here, we show that PhoP mediates the effect of MgrB on steA expression. We also explored whether an additional upstream regulatory component recently described for the E. coli PhoQ/PhoP circuit, the periplasmic oxidant DsbA (48), also modulates expression of steA in S. enterica. Our results show that the effect of a dsbA mutation on steA expression is similar to the effect of an mgrB mutation, and both are PhoP dependent.…”

Section: Discussionmentioning

confidence: 99%

DsbA and MgrB Regulate steA Expression through the Two-Component System PhoQ/PhoP in Salmonella enterica

Cardenal‐Muñoz

Ramos‐Morales

2013

J Bacteriol

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SteA is a protein that can be translocated into host cells through the two virulence-related type III secretion systems that are present in Salmonella enterica. We used the T-POP system to carry out general screens for loci that exhibited activation or repression of a steA::lacZ fusion. These screens identified the histidine kinase PhoQ and the response regulator PhoP as positive regulators of steA. Transcription of this gene is 70 dependent, and the promoter of steA contains a PhoP-binding site that mediates direct regulation by PhoP. Our screens also detected MgrB (also known as YobG) as a negative regulator of the expression of steA. Disruption of the gene encoding the periplasmic disulfide oxidoreductase DsbA or addition of the reducing agent dithiothreitol increases transcription of steA. The effects of MgrB and DsbA on steA are mediated by PhoP. These results suggest that the cellular redox status is a factor contributing to regulation of steA and, probably, other virulence genes regulated by the PhoQ/PhoP two-component system.

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“…Data are mean and SD of three independent experiments. Full-length TcpP and truncated/chimeric TcpP were fused with the T25 and T18 domains of adenylate cyclase (CyaA) from Bordetella pertussis, respectively, and the T25, T18 fusion pairs were introduced into E. coli cyaA mutants (17) or cyaA/dsbA double mutants (35). Cultures were grown at 30°C for 8 h and β-galactosidase activity was measured and reported as Miller Units (36).…”

Section: Fig 2 Bile Salts Regulate Tcpp Activity Through Its Periplmentioning

confidence: 99%

Bile salt–induced intermolecular disulfide bond formation activates Vibrio cholerae virulence

Yang

Liu

Hughes

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

125

173

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To be successful pathogens, bacteria must often restrict the expression of virulence genes to host environments. This requires a physical or chemical marker of the host environment as well as a cognate bacterial system for sensing the presence of a host to appropriately time the activation of virulence. However, there have been remarkably few such signal-sensor pairs identified, and the molecular mechanisms for host-sensing are virtually unknown. By directly applying a reporter strain of Vibrio cholerae, the causative agent of cholera, to a thin layer chromatography (TLC) plate containing mouse intestinal extracts, we found two host signals that activate virulence gene transcription. One of these was revealed to be the bile salt taurocholate. We then show that a set of bile salts cause dimerization of the transmembrane transcription factor TcpP by inducing intermolecular disulfide bonds between cysteine (C)-207 residues in its periplasmic domain. Various genetic and biochemical analyses led us to propose a model in which the other cysteine in the periplasmic domain, C218, forms an inhibitory intramolecular disulfide bond with C207 that must be isomerized to form the active C207-C207 intermolecular bond. We then found bile salt-dependent effects of these cysteine mutations on survival in vivo, correlating to our in vitro model. Our results are a demonstration of a mechanism for direct activation of the V. cholerae virulence cascade by a host signal molecule. They further provide a paradigm for recognition of the host environment in pathogenic bacteria through periplasmic cysteine oxidation.T he human pathogen Vibrio cholerae is the causative agent of the diarrheal disease cholera. The Vibrio life cycle begins with a freeswimming phase in aquatic environments. Human infection normally starts with the ingestion of food or water contaminated with V. cholerae. As it colonizes small intestines of a host and only when it colonizes, V. cholerae produces an array of virulence factors, including cholera toxin (CT), which causes the diarrhea characteristic of cholera and toxin-coregulated pili (TCP), type IV pili required for intestinal colonization both in animal models and in human volunteers (1, 2).Bacterial pathogens have evolved highly sophisticated signal transduction systems to coordinately control the expression of virulence determinants to better infect their hosts. Extensive in vitro studies have revealed details of V. cholerae virulence gene regulation (3): AphA and AphB proteins activate transcription of the transmembrane transcription factor TcpP, which in turn activates toxT transcription together with ToxR, which then completes the cascade by activating toxin and TCP production (Fig. 1A). However, all of the experiments to date used artificial in vitro conditions to induce virulence factor production, leaving unanswered which microenvironmental signals in the intestines activate the V. cholerae virulence cascade. It has been reported that certain environmental conditions such as temperature, oxygen concentra...

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Perturbation of the Oxidizing Environment of the Periplasm Stimulates the PhoQ/PhoP System in Escherichia coli

Cited by 48 publications

References 26 publications

Activation of master virulence regulator PhoP in acidic pH requires the Salmonella -specific protein UgtL

Activation of master virulence regulator PhoP in acidic pH requires the Salmonella -specific protein UgtL

DsbA and MgrB Regulate steA Expression through the Two-Component System PhoQ/PhoP in Salmonella enterica

Bile salt–induced intermolecular disulfide bond formation activates Vibrio cholerae virulence

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