The <scp><i>B</i></scp><i>rucella abortus</i> virulence regulator, <scp>LovhK</scp>, is a sensor kinase in the general stress response signalling pathway

Kim, Hyesook; Willett, Jonathan W.; Jain-Gupta, Neeta; Fiebig, Aretha; Crosson, Sean

doi:10.1111/mmi.12809

Cited by 50 publications

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“…In both E. coli and S. enterica, transcription of YehZ is under the control of the general stress factor, s , and is activated by stress conditions, including nutrient limitation, acidic pH, and hyperosmotic shock (17,20). Analogous to s activation of YehZ expression in E. coli, transcription of B. abortus bab1_0226 is activated by the GSR sigma factor, E1 ( EcfG ) (24,25). Based on similarity to E. coli YehZ in primary structure and regulation, we have designated Bab1_0226 as YehZ.…”

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Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria

et al. 2017

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Brucella abortus E1 is an EcfG family sigma factor that regulates the transcription of dozens of genes in response to diverse stress conditions and is required for maintenance of chronic infection in a mouse model. A putative ATPbinding cassette transporter operon, bab1_0223-bab1_0226, is among the most highly activated gene sets in the E1 regulon. The proteins encoded by the operon resemble quaternary ammonium-compatible solute importers but are most similar in sequence to the broadly conserved YehZYXW system, which remains largely uncharacterized. Transcription of yehZYXW is activated by the general stress sigma factor S in Enterobacteriaceae, which suggests a functional role for this transport system in bacterial stress response across the classes Alphaproteobacteria and Gammaproteobacteria. We present evidence that B. abortus YehZYXW does not function as an importer of known compatible solutes under physiological conditions and does not contribute to the virulence defect of a E1 -null strain. The sole in vitro phenotype associated with genetic disruption of this putative transport system is reduced growth in the presence of high Li ϩ ion concentrations. A crystal structure of B. abortus YehZ revealed a class II periplasmic binding protein fold with significant structural homology to Archaeoglobus fulgidus ProX, which binds glycine betaine. However, the structure of the YehZ ligand-binding pocket is incompatible with high-affinity binding to glycine betaine. This is consistent with weak measured binding of YehZ to glycine betaine and related compatible solutes. We conclude that YehZYXW is a conserved, stress-regulated transport system that is phylogenetically and functionally distinct from quaternary ammonium-compatible solute importers.IMPORTANCE Brucella abortus E1 regulates transcription in response to stressors encountered in its mammalian host and is necessary for maintenance of chronic infection in a mouse model. The functions of the majority of genes regulated by E1 remain undefined. We present a functional/structural analysis of a conserved putative membrane transport system (YehZYXW) whose expression is strongly activated by E1 . Though annotated as a quaternary ammonium osmolyte uptake system, experimental physiological studies and measured ligand-binding properties of the periplasmic binding protein (PBP), YehZ, are inconsistent with this function. A crystal structure of B. abortus YehZ provides molecular insight into differences between bona fide quaternary ammonium osmolyte importers and YehZ-related proteins, which form a distinct phylogenetic and functional group of PBPs.

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Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria

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“…Wild-type B. abortus and strains harboring in-frame deletions of the GSR regulator genes rpoE1 and lovhK were previously challenged with oxidative stress in an effort to characterize the in vitro stress survival deficit of GSR regulatory mutants and to define the GSR transcriptional regulon (48,49). We found that E1 and LovhK mediated a 30-fold increase in transcription of the bab1_1070 gene (wrpA) under oxidative conditions (Fig.…”

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confidence: 95%

“…E1 from an inhibiting interaction with NepR and promotes the transcription of genes involved in B. abortus stress adaptation and chronic infection (48,49). B. abortus wrpA contains a consensus E1 binding site, and its transcription is strongly activated by E1 under oxidative conditions ( Fig.…”

Section: Phyr Phosphorylation By Lovhk Freesmentioning

confidence: 99%

“…Considering that E1 enables growth and survival under a range of nonoptimal growth conditions, including several experienced by B. abortus cells in the mammalian host (5)(6)(7)50, 51), we tested the hypothesis that WrpA functions as an enzyme that facilitates cellular adaptation to particular stress conditions in vitro or in vivo. Unlike strains lacking the primary general stress regulators ( E1 , PhyR, or LovhK) (48,49), a B. abortus ⌬wrpA strain was not deficient in a hydrogen peroxide stress survival assay, nor was it deficient in growth under 1,920 metabolic and drug/chemical conditions we assayed in vitro. Moreover, the ⌬wrpA strain was not attenuated in a macrophage infection model and had no colonization deficit in the spleen in a BALB/c mouse infection model.…”

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“…Analogous to S activation of wrbA expression in E. coli, transcription of wrpA and its homologs is strongly activated by the general stress response (GSR) sigma factor, E1 / EcfG (48,49), in B. abortus and related alphaproteobacteria (19). Considering that E1 enables growth and survival under a range of nonoptimal growth conditions, including several experienced by B. abortus cells in the mammalian host (5)(6)(7)50, 51), we tested the hypothesis that WrpA functions as an enzyme that facilitates cellular adaptation to particular stress conditions in vitro or in vivo.…”

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WrpA Is an Atypical Flavodoxin Family Protein under Regulatory Control of the Brucella abortus General Stress Response System

et al. 2016

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The general stress response (GSR) system of the intracellular pathogen Brucella abortus controls the transcription of approximately 100 genes in response to a range of stress cues. The core genetic regulatory components of the GSR are required for B. abortus survival under nonoptimal growth conditions in vitro and for maintenance of chronic infection in an in vivo mouse model. The functions of the majority of the genes in the GSR transcriptional regulon remain undefined. bab1_1070 is among the most highly regulated genes in this regulon: its transcription is activated 20-to 30-fold by the GSR system under oxidative conditions in vitro. We have solved crystal structures of Bab1_1070 and demonstrate that it forms a homotetrameric complex that resembles those of WrbA-type NADH:quinone oxidoreductases, which are members of the flavodoxin protein family. However, IMPORTANCEBrucella abortus is an etiological agent of brucellosis, which is among the most common zoonotic diseases worldwide. The general stress response (GSR) regulatory system of B. abortus controls the transcription of approximately 100 genes and is required for maintenance of chronic infection in a murine model; the majority of GSR-regulated genes remain uncharacterized. We present in vitro and in vivo functional and structural analyses of WrpA, whose expression is strongly induced by GSR under oxidative conditions. Though WrpA is structurally related to NADH:quinone oxidoreductases, it does not bind redox cofactors in solution, nor does it exhibit oxidoreductase activity in vitro. However, WrpA does affect spleen inflammation in a murine infection model. Our data provide evidence that WrpA forms a new functional class of WrbA/flavodoxin family proteins. Bacterial pathogens face fluctuating chemical and physical challenges in the host environment, including low pH, antimicrobial peptides, nutrient sequestration, and oxidative burst. These conditions can damage essential cellular components, including nucleic acids, proteins, and lipids. As such, bacteria encode a variety of protection mechanisms, including antioxidant enzymes, DNA damage repair systems, and efflux systems (1-4), which enable the cell to resist attacks by the host immune system (5-7).The diverse flavodoxin family, which is composed of enzymes that noncovalently bind a flavin cofactor and transfer electrons between a variety of substrates, can help to maintain cellular redox balance and confer resistance to oxidative stress (8-10). Flavodoxins and flavodoxin-like proteins are also known to promote pathogen virulence and to play a role in host infection and colonization (8,(11)(12)(13)(14)(15)(16)(17)(18), in addition to important roles in enzyme activation and metabolism (15). The flavodoxin-like protein WrbA (tryptophan [W] repressor binding protein) has been described for several microbial species, in which it is proposed to facilitate adaptation to varied chemical changes in the environment (13,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)

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The Extracytoplasmic Function Sigma Factor–mediated Response to Heavy Metal Stress in Caulobacter Crescentus

Lourenço

Gomes

2016

Stress and Environmental Regulation of Gene Expression and Adaptation in Bacteria

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The Brucella abortus virulence regulator, LovhK, is a sensor kinase in the general stress response signalling pathway

Cited by 50 publications

References 50 publications

Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria

Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria

WrpA Is an Atypical Flavodoxin Family Protein under Regulatory Control of the Brucella abortus General Stress Response System

The Extracytoplasmic Function Sigma Factor–mediated Response to Heavy Metal Stress in Caulobacter Crescentus

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