How the PhoP/PhoQ System Controls Virulence and Mg
            <sup>2+</sup>
            Homeostasis: Lessons in Signal Transduction, Pathogenesis, Physiology, and Evolution

Groisman, Eduardo A.; Duprey, Alexandre; Choi, Jeongjoon

doi:10.1128/mmbr.00176-20

Cited by 85 publications

(93 citation statements)

References 419 publications

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“…PhoQ HK in E. coli and Salmonella responds to changes in the membrane. As described in the previous section, the periplasmic sensor domain of PhoQ senses divalent cations, acidic pH, and antimicrobial peptides [58]. In addition to these signals, Yuan et al found that an osmotic upshift activates the PhoQ/PhoP system [96].…”

Section: Intramolecular Sensingmentioning

confidence: 91%

“…PDC ligand-binding sites are not only present in conserved clefts. PhoQ is the HK of the PhoQ/PhoP TCS, which plays an important role in the regulation of virulence in gram negative bacteria such as Salmonella [58]. PhoQ is a multisensing kinase that responds to multiple signals, such as divalent cations, low pH, osmotic upshifts, and cationic antimicrobial peptides [58].…”

Section: Sensing By a Pas-like Domainmentioning

confidence: 99%

“…PhoQ is the HK of the PhoQ/PhoP TCS, which plays an important role in the regulation of virulence in gram negative bacteria such as Salmonella [58]. PhoQ is a multisensing kinase that responds to multiple signals, such as divalent cations, low pH, osmotic upshifts, and cationic antimicrobial peptides [58]. A comparison between PhoQ-PDC and CitA-PDC domains shows that the former has the addition of two α-helices and an absence of the cleft region [27,28].…”

Section: Sensing By a Pas-like Domainmentioning

confidence: 99%

“…Interaction between TM helices is also necessary for the Salmonella and E. coli membrane protein, MgrB, to modulate the activity of PhoQ HK. The PhoQ/PhoP TCS is critical for virulence in various gram negative pathogens, such as Salmonella and K. pneumonia [58]. PhoQ/PhoP directly regulates mgrB expression.…”

Section: Intramolecular Signal Integrationmentioning

confidence: 99%

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Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Ishii

Eguchi

2021

Biomolecules

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Two-component signal transduction systems (TCSs) are widely conserved in bacteria to respond to and adapt to the changing environment. Since TCSs are also involved in controlling the expression of virulence, biofilm formation, quorum sensing, and antimicrobial resistance in pathogens, they serve as candidates for novel drug targets. TCSs consist of a sensor histidine kinase (HK) and its cognate response regulator (RR). Upon perception of a signal, HKs autophosphorylate their conserved histidine residues, followed by phosphotransfer to their partner RRs. The phosphorylated RRs mostly function as transcriptional regulators and control the expression of genes necessary for stress response. HKs sense their specific signals not only in their extracytoplasmic sensor domain but also in their cytoplasmic and transmembrane domains. The signals are sensed either directly or indirectly via cofactors and accessory proteins. Accumulating evidence shows that a single HK can sense and respond to multiple signals in different domains. The underlying molecular mechanisms of how HK activity is controlled by these signals have been extensively studied both biochemically and structurally. In this article, we introduce the wide diversity of signal perception in different domains of HKs, together with their recently clarified structures and molecular mechanisms.

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Section: Intramolecular Sensingmentioning

confidence: 91%

Section: Sensing By a Pas-like Domainmentioning

confidence: 99%

Section: Sensing By a Pas-like Domainmentioning

confidence: 99%

Section: Intramolecular Signal Integrationmentioning

confidence: 99%

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Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Ishii

Eguchi

2021

Biomolecules

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“…In this study, we used Enterobacter cloacae as a model Gram-negative pathogen to investigate genetic factors that contribute to bacterial tolerance to meropenem, which is used as a last-resort β-lactam to treat multidrug resistant bacterial infections [15][16][17]. We first show that tolerance is dependent on outer membrane modifications (specifically 4-amino-4-deoxy-Laminoarabinose [L-Ara4N]) induced by the PhoPQ TCS, an important cell envelope stress sensor that has previously been shown to respond to magnesium limitation, cationic antimicrobial peptide exposure, osmotic challenge, and pH changes [18]. Both PhoPQ regulon transcription and modification of the lipopolysaccharide lipid A domain are induced by meropenem treatment, suggesting a specific response to perturbations of PG synthesis in E. cloacae.…”

Section: Introductionmentioning

confidence: 99%

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

et al. 2022

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Antibiotic tolerance is an understudied potential contributor to antibiotic treatment failure and the emergence of multidrug-resistant bacteria. The molecular mechanisms governing tolerance remain poorly understood. A prominent type of β-lactam tolerance relies on the formation of cell wall-deficient spheroplasts, which maintain structural integrity via their outer membrane (OM), an asymmetric lipid bilayer consisting of phospholipids on the inner leaflet and a lipid-linked polysaccharide (lipopolysaccharide, LPS) enriched in the outer monolayer on the cell surface. How a membrane structure like LPS, with its reliance on mere electrostatic interactions to maintain stability, is capable of countering internal turgor pressure is unknown. Here, we have uncovered a novel role for the PhoPQ two-component system in tolerance to the β-lactam antibiotic meropenem in Enterobacterales. We found that PhoPQ is induced by meropenem treatment and promotes an increase in 4-amino-4-deoxy-L-aminoarabinose [L-Ara4N] modification of lipid A, the membrane anchor of LPS. L-Ara4N modifications likely enhance structural integrity, and consequently tolerance to meropenem, in several Enterobacterales species. Importantly, mutational inactivation of the negative PhoPQ regulator mgrB (commonly selected for during clinical therapy with the last-resort antibiotic colistin, an antimicrobial peptide [AMP]) results in dramatically enhanced tolerance, suggesting that AMPs can collaterally select for meropenem tolerance via stable overactivation of PhoPQ. Lastly, we identify histidine kinase inhibitors (including an FDA-approved drug) that inhibit PhoPQ-dependent LPS modifications and consequently potentiate meropenem to enhance lysis of tolerant cells. In summary, our results suggest that PhoPQ-mediated LPS modifications play a significant role in stabilizing the OM, promoting survival when the primary integrity maintenance structure, the cell wall, is removed.

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Crystal structure of the catalytic ATP‐binding domain of the PhoR sensor histidine kinase

2023

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The two-component regulatory system (TCS) is a major regulatory system in bacteria that occurs in response to environmental changes and involves the sensor histidine kinase (HK) protein and response regulator (RR) protein. Among the TCSs, PhoR/ PhoB is crucial for bacteria to adapt to changes in environmental phosphate concentrations. In addition, recent studies have shown that PhoR binding to the MgtC virulence factor activates phosphate transport for normal pathogenesis. In this work, we determined the crystal structure of the catalytic ATP binding domain of the PhoR sensor histidine kinase from Vibrio cholera, compared the structure with the known HK protein structures and discussed the potential binding interface with MgtC.

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How the PhoP/PhoQ System Controls Virulence and Mg ²⁺ Homeostasis: Lessons in Signal Transduction, Pathogenesis, Physiology, and Evolution

Cited by 85 publications

References 419 publications

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

Crystal structure of the catalytic ATP‐binding domain of the PhoR sensor histidine kinase

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How the PhoP/PhoQ System Controls Virulence and Mg 2+ Homeostasis: Lessons in Signal Transduction, Pathogenesis, Physiology, and Evolution

Cited by 85 publications

References 419 publications

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

Crystal structure of the catalytic ATP‐binding domain of the PhoR sensor histidine kinase

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How the PhoP/PhoQ System Controls Virulence and Mg ²⁺ Homeostasis: Lessons in Signal Transduction, Pathogenesis, Physiology, and Evolution