Signaling by two-component system noncognate partners promotes intrinsic tolerance to polymyxin B in uropathogenic
            <i>Escherichia coli</i>

Guckes, Kirsten R.; Breland, Erin J.; Zhang, Ellisa W.; Hanks, Sarah C.; Gill, Navleen K.; Algood, Holly M. Scott; Schmitz, Jonathan E.; Stratton, Charles W.; Hadjifrangiskou, Maria

doi:10.1126/scisignal.aag1775

Cited by 40 publications

(62 citation statements)

References 58 publications

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“…The same studies also elucidated that phosphorylated PmrA (PmrAϳP) and QseB (QseBϳP) coregulate downstream targets, which in Salmonella spp. are exclusively controlled by PmrA (11). Together, these studies provided evidence of two TCSs, whose partner proteins interact to mediate a particular response.…”

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confidence: 81%

“…In the absence of QseC, QseBϳP binds and induces the expression of qseBC, resulting in increased levels of qseB steady-state transcript (11,12,15). Quantitative PCR (qPCR) analysis demonstrated that introduction of the mutated qseC sequences suppressed the aberrant expression of qseB (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The observation that PmrB-QseB protein-protein interactions are nearly as robust as QseC-QseB interactions (15) raised the hypothesis that PmrB and QseB physiologically interact to mediate stimulus responses in wild-type (WT) UPEC. Subsequent studies investigating the hypothesized PmrB-QseB interaction in UPEC, revealed that presence of the PmrB activating signal ferric iron (Fe 3ϩ ) leads to phosphorylation of both PmrA and QseB by PmrB and results in elevated tolerance of UPEC to polymyxin B (11). The same studies also elucidated that phosphorylated PmrA (PmrAϳP) and QseB (QseBϳP) coregulate downstream targets, which in Salmonella spp.…”

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confidence: 84%

“…The presence of QseC is absolutely required for PmrB-QseB-PmrA-mediated stimulus response to Fe 3ϩ (11). To determine how the QseC_H246 variants would influence the Fe 3ϩ stimulus response, we cultured UTI89ΔqseC::QseC WT , UTI89ΔqseC::QseC_H246A, UTI89ΔqseC::QseC_H246D, and UTI89ΔqseC:: QseC_H246L in N-minimal medium as previously described (11,19,20) in the presence or absence of Fe 3ϩ and monitored the qseB transcriptional surge using qPCR. UTI89ΔqseC::QseC WT exhibited a qseBC transcriptional surge in response to stimulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have also elucidated examples in which protein-protein interactions occur across two TCSs, like in the case of the QseBC and PmrAB TCSs (11). Previous studies with several bacterial pathogens identified that deletion of the qseC gene, which codes for the QseC histidine kinase, attenuates bacterial virulence (12)(13)(14).…”

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confidence: 99%

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The Histidine Residue of QseC Is Required for Canonical Signaling between QseB and PmrB in Uropathogenic Escherichia coli

et al. 2017

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Two-component systems are prototypically comprised of a histidine kinase (sensor) and a response regulator (responder). The sensor kinases autophosphorylate at a conserved histidine residue, acting as a phosphodonor for subsequent phosphotransfer to and activation of a cognate response regulator. In rare cases, the histidine residue is also essential for response regulator dephosphorylation via a reverse-phosphotransfer reaction. In this work, we present an example of a kinase that relies on reverse phosphotransfer to catalyze the dephosphorylation of its cognate partner. The QseC sensor kinase is conserved across several Gram-negative pathogens; its interaction with its cognate partner QseB is critical for maintaining pathogenic potential. Here, we demonstrate that QseC-mediated dephosphorylation of QseB occurs via reverse phosphotransfer. In previous studies, we demonstrated that, in uropathogenic Escherichia coli, exposure to high concentrations of ferric iron (Fe 3ϩ ) stimulates the PmrB sensor kinase. This stimulation, in turn, activates the cognate partner, PmrA, and noncognate QseB to enhance tolerance to polymyxin B. We demonstrate that in the absence of signal, kinase-inactive QseC variants, in which the H246 residue was changed to alanine (A) aspartate (D) or leucine (L), rescued a ΔqseC deletion mutant, suggesting that QseC can control QseB activation via a mechanism that is independent of reverse phosphotransfer. However, in the presence of Fe 3ϩ , the same QseC variants were unable to mediate a wild-type stimulus response, indicating that QseC-mediated dephosphorylation is required for maintaining proper QseB-PmrB-PmrA interactions.IMPORTANCE Two-component signaling networks constitute one of the predominant methods by which bacteria sense and respond to their changing environments. Two-component systems allow bacteria to thrive and survive in a number of different environments, including within a human host. Uropathogenic Escherichia coli, the causative agent of urinary tract infections, rely on two interacting two-component systems, QseBC and PmrAB, to induce intrinsic resistance to the colistin antibiotic polymyxin B, which is a last line of defense drug. The presence of one sensor kinase, QseC, is required to regulate the interaction between the other sensor kinase, PmrB and the response regulators from both systems, QseB and PmrA, effectively creating a "four-component" system required for virulence. Understanding the important role of the sensor kinase QseC will provide insight into additional ways to therapeutically target uropathogens that harbor these signaling systems.KEYWORDS two-component systems, UPEC, QseBC, PmrAB, cross-regulation, histidine kinase, QseC, ferric iron, two-component regulatory systems

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confidence: 81%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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The Histidine Residue of QseC Is Required for Canonical Signaling between QseB and PmrB in Uropathogenic Escherichia coli

et al. 2017

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Evidence of Cross-Regulation in Two Closely Related Pyruvate-Sensing Systems in Uropathogenic Escherichia coli

et al. 2018

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Two-component systems (TCSs) dictate many bacterial responses to environmental change via the activation of a membrane-embedded sensor kinase, which has molecular specificity for a cognate response regulator protein. However, although the majority of TCSs operate through seemingly strict cognate protein-protein interactions, there have been several reports of TCSs that violate this classical model of signal transduction. Our group has recently demonstrated that some of these cross-interacting TCSs function in a manner that imparts a fitness advantage to bacterial pathogens. In this study, we describe interconnectivity between the metabolite-sensing TCSs YpdA/YpdB and BtsS/BtsR in uropathogenic Escherichia coli (UPEC). The YpdA/YpdB and BtsS/BtsR TCSs have been previously reported to interact in K12 E. coli, where they alter the expression of putative transporter genes yhjX and yjiY, respectively. These target genes are both upregulated in UPEC during acute and chronic murine models of urinary tract infection, as well as in response to pyruvate and serine added to growth media in vitro. Here, we show that proper regulation of yhjX in UPEC requires the presence of all components from both of these TCSs. By utilizing plasmid-encoded luciferase reporters tracking the activity of the yhjX and yjiY promoters, we demonstrate that deletions in one TCS substantially alter transcriptional activity of the opposing system's target gene. However, unlike in K12 E. coli, single gene deletions in the YpdA/YpdB system do not alter yjiY gene expression in UPEC, suggesting that niche and lifestyle-specific pressures may be selecting for differential cross-regulation of TCSs in pathogenic and non-pathogenic E. coli.

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Identification of the cognate response regulator of the orphan histidine kinase OhkA involved in both secondary metabolism and morphological differentiation in Streptomyces coelicolor

Zheng

et al. 2021

Appl Microbiol Biotechnol

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In the model actinomycete strain, Streptomyces coelicolor, an orphan histidine kinase (HK) named OhkA (encoded by SCO1596), which belongs to bacterial two-component regulatory systems (TCSs), has been identified as being involved in the regulation of both antibiotic biosynthesis and morphological development. However, its cognate response regulator (RR) remains unknown due to its isolated genetic location on the genome, which impedes the elucidation of the mechanism underlying OhkAmediated regulation. Here, we identified the orphan RR OrrA (encoded by SCO3008) as the cognate RR of OhkA according to mutant phenotypic changes, transcriptomics analysis, and bacterial two-hybrid experiment. Considering that the partner RR of the orphan HK is also orphan, a library of mutants with in-frame individual deletion of these functionally unknown orphan RRencoding genes were generated. Through phenotypic analysis, it was found that the ΔorrA mutant exhibited similar phenotypic changes as that of the ΔohkA mutant, showing increased production of actinorhodin (ACT) and undecylprodigiosin (RED), and pink colony surface. Further transcriptomics analysis showed these two mutants exhibited highly similar transcriptomics profiles. Finally, the direct interaction between OhkA and OrrA was revealed by bacterial two-hybrid system. The identification of the partner RR of OhkA lays a good foundation for an in-depth elucidation of the molecular mechanism underlying OhkA-mediated regulation of development and antibiotic biosynthesis in Streptomyces. Key points• OrrA was identified as the partner RR of the orphan histidine kinase OhkA.• The ΔorrA and ΔohkA mutants showed similar phenotype and transcriptomic profiling.• Specific interaction of OrrA and OhkA was revealed by bacterial two-hybrid system.

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Signaling by two-component system noncognate partners promotes intrinsic tolerance to polymyxin B in uropathogenic Escherichia coli

Cited by 40 publications

References 58 publications

The Histidine Residue of QseC Is Required for Canonical Signaling between QseB and PmrB in Uropathogenic Escherichia coli

The Histidine Residue of QseC Is Required for Canonical Signaling between QseB and PmrB in Uropathogenic Escherichia coli

Evidence of Cross-Regulation in Two Closely Related Pyruvate-Sensing Systems in Uropathogenic Escherichia coli

Identification of the cognate response regulator of the orphan histidine kinase OhkA involved in both secondary metabolism and morphological differentiation in Streptomyces coelicolor

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