The CtrA phosphorelay integrates differentiation and communication in the marine alphaproteobacterium Dinoroseobacter shibae

Wang, Hui; Ziesche, Lisa; Frank, Oliver; Michael, Victoria; Martin, Madeleine; Petersen, Jörn; Schulz, Stefan; Wagner‐Döbler, Irene; Tomasch, Jürgen

doi:10.1186/1471-2164-15-130

Cited by 46 publications

(75 citation statements)

References 55 publications

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“…So far, CtrA was shown to control motility in all Alphaproteobacteria in which it was tested (Wu and Newton, ; Lang and Beatty, ; Miller and Belas, ; Belas et al ., ; Greene et al ., ; Zan et al ., ; De Nisco et al ., ; Wang et al ., ). Our data suggest that CtrA is the master regulator of flagella synthesis in S. melonis , initiating a cascade of regulation that involves σ 54 and the σ 54 ‐dependent regulator FleT for the regulation of class III genes, and FliA for class IV flagellin genes (Fig E).…”

Section: Discussionmentioning

confidence: 97%

The branched CcsA/CckA‐ChpT‐CtrA phosphorelay of Sphingomonas melonis controls motility and biofilm formation

Francez‐Charlot

Kaczmarczyk

Vorholt

2015

Molecular Microbiology

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SummaryThe CckA-ChpT-CtrA phosphorelay is central to the regulation of the cell cycle in Caulobacter crescentus. The three proteins are conserved in Alphaproteobacteria, but little is known about their roles in most members of this class. Here, we characterized the system in Sphingomonas melonis. We found that the transcription factor CtrA is the master regulator of flagella synthesis genes, the hierarchical transcriptional organization of which is herein described. CtrA also regulates genes involved in exopolysaccharide synthesis and cyclic-di-GMP signaling, and is important for biofilm formation. In addition, the ctrA mutant exhibits an aberrant morphology, suggesting a role for CtrA in cell division. An analysis of the regulation of CtrA indicates that the phosphorelay composed of CckA and ChpT is conserved and that the absence of the bifunctional kinase/phosphatase CckA apparently results in overactivation of CtrA through ChpT. Suppressors of this phenotype identified the hybrid histidine kinase CcsA. Phosphorelays initiated by CckA or CcsA were reconstituted in vitro, suggesting that in S. melonis, CtrA phosphorylation is controlled by a branched pathway upstream of ChpT. This study thus suggests that signals can directly converge at the level of ChpT phosphorylation through multiple hybrid kinases to coordinate a number of important physiological processes.

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Section: Discussionmentioning

confidence: 97%

The branched CcsA/CckA‐ChpT‐CtrA phosphorelay of Sphingomonas melonis controls motility and biofilm formation

Francez‐Charlot

Kaczmarczyk

Vorholt

2015

Molecular Microbiology

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“…However, there is notable diversity in the transcriptional output of this system across the clade (10)(11)(12)(13), which likely reflects the breadth of niches inhabited by these species (14). The function of this system in Brucella abortus, which is capable of infecting, growing, and replicating inside mammalian cells, is poorly understood, although previous studies of Brucella CtrA have revealed a possible role in the control of cell division (15).…”

mentioning

confidence: 99%

Structural asymmetry in a conserved signaling system that regulates division, replication, and virulence of an intracellular pathogen

Willett

Herrou

Briegel

et al. 2015

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

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We have functionally and structurally defined an essential protein phosphorelay that regulates expression of genes required for growth, division, and intracellular survival of the global zoonotic pathogen Brucella abortus. Our study delineates phosphoryl transfer through this molecular pathway, which initiates from the sensor kinase CckA and proceeds through the ChpT phosphotransferase to two regulatory substrates: CtrA and CpdR. Genetic perturbation of this system results in defects in cell growth and division site selection, and a specific viability deficit inside human phagocytic cells. Thus, proper control of B. abortus division site polarity is necessary for survival in the intracellular niche. We further define the structural foundations of signaling from the central phosphotransferase, ChpT, to its response regulator substrate, CtrA, and provide evidence that there are at least two modes of interaction between ChpT and CtrA, only one of which is competent to catalyze phosphoryltransfer. The structure and dynamics of the active site on each side of the ChpT homodimer are distinct, supporting a model in which quaternary structure of the 2:2 ChpT-CtrA complex enforces an asymmetric mechanism of phosphoryl transfer between ChpT and CtrA. Our study provides mechanistic understanding, from the cellular to the atomic scale, of a conserved transcriptional regulatory system that controls the cellular and infection biology of B. abortus. More generally, our results provide insight into the structural basis of two-component signal transduction, which is broadly conserved in bacteria, plants, and fungi.rucellosis, caused by Brucella spp., is among the most common zoonotic diseases worldwide (1). These intracellular pathogens are estimated to cause at least 500,000 new human infections each year and, in areas of Africa, Asia, and South America, inflict significant agricultural losses due to decreased livestock production (2, 3). Survival of Brucella within mammals is linked to their ability to infect and survive inside professional phagocytic cells (2). If left untreated in human hosts, Brucella eventually spread to multiple tissue types, which can lead to a range of debilitating chronic sequelae including reticuloendothelial, cardiovascular, gastrointestinal, and neurological damage.Brucella are members of the α-proteobacteria, a diverse class of Gram-negative species adapted for growth across a range of environmental conditions including plant surfaces and roots, aquatic and soil ecosystems, and the interior of mammalian cells (4, 5). Among the central regulatory systems controlling the α-proteobacterial cell cycle is a multistep phosphorelay composed of four proteins: (i) the hybrid sensor histidine kinase (HK) CckA, (ii) the histidine phosphotransferase ChpT, (iii) the DNA-binding response regulator CtrA, and (iv) the phospho-receiver protein CpdR (Fig. 1). Our current understanding of this conserved regulatory system is based largely on studies of the related aquatic bacterium Caulobacter crescentus (6, 7). In Ca...

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“…Our results show that a single mutation in CckA is able to turn on the Fla2 system and imply that the proteins homologous to CtrA and ChpT should be involved in this phenomenon. The idea that CtrA and ChpT could also control the expression of the Fla2 genes is based on the fact that these proteins together with CckA are implicated in the expression of the flagellar genes in other bacteria (14)(15)(16)(17)(18)(19). Therefore, we searched the genome of R. sphaeroides for genes encoding these proteins and found that RSWS8N_03320 (RSP_2621 in 2.4.1) encodes the response regulator CtrA, whereas RSWS8N_16219 (RSP_3825) encodes the homologue of the phosphotransfer protein ChpT.…”

Section: Resultsmentioning

confidence: 99%

“…In this group of bacteria, there is no evidence regarding the control of the activity of CckA, but it has been reported that the expression of cckA, chpT, and/or ctrA is reduced in quorum sensing mutants in Ruegeria sp. strain KLH11, Dinoroseobacter shibae, and Rhodobacter capsulatus (16,17,19,20). However, in Ruegeria sp.…”

mentioning

confidence: 97%

“…For some species of this bacterial group, it has been reported that CtrA does not control the cell cycle, but it controls directly or indirectly the expression of the flagellar genes (14)(15)(16)(17)(18)(19). In this group of bacteria, there is no evidence regarding the control of the activity of CckA, but it has been reported that the expression of cckA, chpT, and/or ctrA is reduced in quorum sensing mutants in Ruegeria sp.…”

mentioning

confidence: 99%

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The Flagellar Set Fla2 in Rhodobacter sphaeroides Is Controlled by the CckA Pathway and Is Repressed by Organic Acids and the Expression of Fla1

et al. 2015

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Rhodobacter sphaeroides has two different sets of flagellar genes. Under the growth conditions commonly used in the laboratory, the expression of the fla1 set is constitutive, whereas the fla2 genes are not expressed. Phylogenetic analyses have previously shown that the fla1 genes were acquired by horizontal transfer from a gammaproteobacterium and that the fla2 genes are endogenous genes of this alphaproteobacterium. In this work, we characterized a set of mutants that were selected for swimming using the Fla2 flagella in the absence of the Fla1 flagellum (Fla2 ؉ strains). We determined that these strains have a single missense mutation in the histidine kinase domain of CckA. The expression of these mutant alleles in a Fla1؊ strain allowed fla2-dependent motility without selection. Motility of the Fla2 ؉ strains is also dependent on ChpT and CtrA. The mutant versions of CckA showed an increased autophosphorylation activity in vitro. Interestingly, we found that cckA is transcriptionally repressed by the presence of organic acids, suggesting that the availability of carbon sources could be a part of the signal that turns on this flagellar set. Evidence is presented showing that reactivation of fla1 gene expression in the Fla2؉ background strongly reduces the number of cells with Fla2 flagella. More than 40 genes are involved in the biogenesis and functioning of the bacterial flagellum. This structure has three major subcomponents, the basal body, the hook, and the filament. The basal body contains the export apparatus, an inner membrane ring (MS ring), a periplasmic ring (P ring), and, depending on the species, an outer membrane ring (L ring). The basal body also includes the flagellar motor and a rod that expands from the MS ring and crosses the L and P rings. The hook is the first extracellular structure that is assembled; it connects the basal body with the flagellar filament that is formed by thousands of flagellin subunits (reviewed in references 1-3).In most bacterial species, the expression of the flagellar genes is highly regulated and frequently follows a hierarchical order in which the late genes are expressed until the early genes, that are higher in the hierarchy, are expressed. At the top of the hierarchy, a transcriptional regulator is responsible for the expression of the genes required to assemble the early flagellar structures that are located in the cytoplasm (i.e., export apparatus), in the cytoplasmic membrane (i.e., MS ring), and, depending on the hierarchy, in the periplasm (i.e., P ring), the outer membrane (i.e., L ring), and the extracellular milieu (i.e., hook). Within this class, additional transcription factors are expressed. These proteins are required to transcribe the late genes, such as fliC (flagellin), fliD (filament cap), and fliS

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The CtrA phosphorelay integrates differentiation and communication in the marine alphaproteobacterium Dinoroseobacter shibae

Cited by 46 publications

References 55 publications

The branched CcsA/CckA‐ChpT‐CtrA phosphorelay of Sphingomonas melonis controls motility and biofilm formation

The branched CcsA/CckA‐ChpT‐CtrA phosphorelay of Sphingomonas melonis controls motility and biofilm formation

Structural asymmetry in a conserved signaling system that regulates division, replication, and virulence of an intracellular pathogen

The Flagellar Set Fla2 in Rhodobacter sphaeroides Is Controlled by the CckA Pathway and Is Repressed by Organic Acids and the Expression of Fla1

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