<i>In vivo</i> phosphorylation dynamics of the <i><scp>B</scp>ordetella pertussis</i> virulence‐controlling response regulator <scp>BvgA</scp>

Boulanger, Alice; Chen, Qing; Hinton, Deborah M.; Stibitz, Scott

doi:10.1111/mmi.12177

Cited by 46 publications

(82 citation statements)

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“…This system is coordinated by the intracellular level of phosphorylated BvgA (BvgA~P) (11,12). It can be modulated by changing growth conditions, which can be divided into three modes [Bvg(ϩ), Bvg(i), and Bvg(Ϫ)] (13; reviewed in references 14 and 15).…”

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confidence: 99%

“…Our results are consistent with the idea that metabolic changes in the Bvg(Ϫ) mode may be participating in bacterial survival, transmission, and/or persistence. BvgA is present at higher concentrations and is primarily in the form of BvgA~P (11). Illumina sequencing data were analyzed using CLC Genomic Workbench after normalization with total reads, comparing gene expression of the following experimental sets: set 1, WT with or without MgSO 4 ; set 2, WT versus ΔbvgAS mutant in the absence of MgSO 4 ; and set 3, ΔbvgAS mutant with or without MgSO 4 (Table S1A).…”

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The BvgAS Regulon of Bordetella pertussis

Moon

Bonocora

Kim

et al. 2017

mBio

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120

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Nearly all virulence factors in Bordetella pertussis are activated by a master two-component system, BvgAS, composed of the sensor kinase BvgS and the response regulator BvgA. When BvgS is active, BvgA is phosphorylated (BvgA~P), and virulence-activated genes (vags) are expressed [Bvg(ϩ) mode]. When BvgS is inactive and BvgA is not phosphorylated, virulence-repressed genes (vrgs) are induced [Bvg(Ϫ) mode]. Here, we have used transcriptome sequencing (RNA-seq) and reverse transcription-quantitative PCR (RT-qPCR) to define the BvgAS-dependent regulon of B. pertussis Tohama I. Our analyses reveal more than 550 BvgA-regulated genes, of which 353 are newly identified. BvgA-activated genes include those encoding two-component systems (such as kdpED), multiple other transcriptional regulators, and the extracytoplasmic function (ECF) sigma factor brpL, which is needed for type 3 secretion system (T3SS) expression, further establishing the importance of BvgA~P as an apex regulator of transcriptional networks promoting virulence. Using in vitro transcription, we demonstrate that the promoter for brpL is directly activated by BvgA~P. BvgA-FeBABE cleavage reactions identify BvgA~P binding sites centered at positions Ϫ41.5 and Ϫ63.5 in bprL. Most importantly, we show for the first time that genes for multiple and varied metabolic pathways are significantly upregulated in the B. pertussis Bvg(Ϫ) mode. These include genes for fatty acid and lipid metabolism, sugar and amino acid transporters, pyruvate dehydrogenase, phenylacetic acid degradation, and the glycolate/glyoxylate utilization pathway. Our results suggest that metabolic changes in the Bvg(Ϫ) mode may be participating in bacterial survival, transmission, and/or persistence and identify over 200 new vrgs that can be tested for function.IMPORTANCE Within the past 20 years, outbreaks of whooping cough, caused by Bordetella pertussis, have led to respiratory disease and infant mortalities, despite good vaccination coverage. This is due, at least in part, to the introduction of a less effective acellular vaccine in the 1990s. It is crucial, then, to understand the molecular basis of B. pertussis growth and infection. The two-component system BvgA (response regulator)/BvgS (histidine kinase) is the master regulator of B. pertussis virulence genes. We report here the first RNA-seq analysis of the BvgAS regulon in B. pertussis, revealing that more than 550 genes are regulated by BvgAS. We show that genes for multiple and varied metabolic pathways are highly regulated in the Bvg(Ϫ) mode (absence of BvgA phosphorylation). Our results suggest that metabolic changes in the Bvg(Ϫ) mode may be participating in bacterial survival, transmission, and/or persistence.

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The BvgAS Regulon of Bordetella pertussis

Moon

Bonocora

Kim

et al. 2017

mBio

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120

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“…Shift of BvgS Activity upon Nicotinate Addition-To directly follow the enzymatic activity of BvgS after nicotinate addition, we used a Phos-tag assay that detects the kinase and phosphotransferase activities of BvgS via the level of phosphorylated BvgA (BvgAϳP) (30). Nicotinate was added to the bacterial cultures, and aliquots were taken after increasing periods of time.…”

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Signal Transduction by BvgS Sensor Kinase

Dupré

Lesne

Guérin

et al. 2015

Journal of Biological Chemistry

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“…Conservation across species of phosphorylation sites in enzymes from the central carbon metabolism in pathways for glycolysis, pentose phosphate and the tricarboxylic acid (TCA) cycle, suggests that phosphorylation plays a pivotal role in regulating central carbon metabolism. Previous studies have also linked S/T/Y phosphorylation to regulation of cell differentiation [29], physiology [42,43], stress [44,45], virulence and pathogenicity [46][47][48][49][50].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Global dynamics of Escherichia coli phosphoproteome in central carbon metabolism under changing culture conditions

Lim

Marcellin

Jacob

et al. 2015

Journal of Proteomics

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Little is known about the role of global phosphorylation events in the control of prokaryote metabolism. By performing a detailed analysis of all protein phosphorylation events previously reported in Escherichia coli, dynamic changes in protein phosphorylation were elucidated under three different culture conditions. Using scheduled reaction monitoring, the phosphorylation ratios of 82 peptides corresponding to 71 proteins were quantified to establish whether serine (S), threonine (T) and tyrosine (Y) phosphorylation events displayed a dynamic profile under changing culture conditions. The ratio of phosphorylation for 23 enzymes from central carbon metabolism was found to be dynamic. The data presented contributes to our understanding of the global role of phosphorylation in bacterial metabolism and highlight that phosphorylation is an important, yet poorly understood, regulatory mechanism of metabolism control in bacteria. Biological significanceThe findings in this manuscript provide novel scientific knowledge about protein phosphorylation in dynamic regulation of the central carbon metabolism of E. coli. Evidence has accumulated confirming that phosphorylation is prevalently present in bacteria and has important regulatory roles of control of the central carbon metabolism. This investigation goes beyond data collections and shows that protein phosphorylation is quantitatively significant and varies under changing culture conditions.

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In vivo phosphorylation dynamics of the Bordetella pertussis virulence‐controlling response regulator BvgA

Cited by 46 publications

References 47 publications

The BvgAS Regulon of Bordetella pertussis

The BvgAS Regulon of Bordetella pertussis

Signal Transduction by BvgS Sensor Kinase

Global dynamics of Escherichia coli phosphoproteome in central carbon metabolism under changing culture conditions

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