Brucella melitensis MucR, an Orthologue of Sinorhizobium meliloti MucR, Is Involved in Resistance to Oxidative, Detergent, and Saline Stresses and Cell Envelope Modifications

Mirabella, Aurélie; Terwagne, Matthieu; Zygmunt, Michel S.; Cloeckaert, Axel; Bolle, Xavier De; Letesson, Jean‐Jacques

doi:10.1128/jb.01336-12

Cited by 51 publications

(78 citation statements)

References 92 publications

(104 reference statements)

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“…The studies presented here, for instance, demonstrate that mucR expression in B. abortus 2308 is controlled by repressive autoregulation, and studies by Mirabella et al suggest that mucR expression in B. melitensis 16 M may be induced by osmotic stress (45). The results presented in this report also support the contention that the activity of MucR-type transcriptional regulators is dependent upon the availability of divalent cations (22).…”

Section: Fig 6 Autoregulation Of Mucr Expression In Brucella Abortus supporting

confidence: 79%

“…Recent experiments do, however, indicate that a B. melitensis 16 M-derived mucR mutant has a more subtle growth defect than its B. abortus counterpart. Specifically, the B. melitensis mucR mutant enters stationary phase more rapidly and at a lower cell density than the 16 M parental strain (45). The genetic basis for the growth defect exhibited by the B. abortus mucR mutant is not readily apparent from the set of MucR-regulated genes identified in this study.…”

Section: Discussionmentioning

confidence: 72%

“…As mentioned previously in this report, although the LPS moieties of both the B. abortus and B. melitensis mucR mutants retain their O chains, experimental evidence has been obtained with both of these mutants suggesting that these LPS molecules are not entirely "wild type" in structure, as there is a defect in the core of the LPS produced by Brucella mucR mutants (Fig. 3C) (45). Thus, another important component of understanding the role of MucR in the virulence of Brucella strains will be to determine precisely what role this transcriptional regulator plays in the proper expression of their LPS biosynthesis and modification genes.…”

Section: Fig 6 Autoregulation Of Mucr Expression In Brucella Abortus mentioning

confidence: 67%

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Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

et al. 2013

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The Ros-type regulator MucR is one of the few transcriptional regulators that have been linked to virulence in Brucella. Here, we show that a Brucella abortus in-frame mucR deletion strain exhibits a pronounced growth defect during in vitro cultivation and, more importantly, that the mucR mutant is attenuated in cultured macrophages and in mice. The genetic basis for the attenuation of Brucella mucR mutants has not been defined previously, but in the present study the genes regulated by MucR in B. abortus have been elucidated using microarray analysis and real-time reverse transcription-PCR (RT-PCR). In B. abortus 2308, MucR regulates a wide variety of genes whose products may function in establishing and maintaining cell envelope integrity, polysaccharide biosynthesis, iron homeostasis, genome plasticity, and transcriptional regulation. Particularly notable among the MucRregulated genes identified is arsR6 (nolR), which encodes a transcriptional regulator previously linked to virulence in Brucella melitensis 16 M. Importantly, electrophoretic mobility shift assays (EMSAs) determined that a recombinant MucR protein binds directly to the promoter regions of several genes repressed by MucR (including arsR6 [nolR]), and in Brucella, as in other alphaproteobacteria, MucR binds to its own promoter to repress expression of the gene that encodes it. Overall, these studies have uncovered the diverse genetic regulon of MucR in Brucella, and in doing so this work has begun to define the MucR-controlled genetic circuitry whose misregulation contributes to the virulence defect of Brucella mucR mutants.

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Section: Fig 6 Autoregulation Of Mucr Expression In Brucella Abortus supporting

confidence: 79%

Section: Discussionmentioning

confidence: 72%

Section: Fig 6 Autoregulation Of Mucr Expression In Brucella Abortus mentioning

confidence: 67%

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Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

et al. 2013

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“…It has been estimated that Ͼ5% of bacterial proteins bind Zn (9), and several Zn-containing proteins that are important for the basic physiology and virulence of Brucella strains have been identified (10,11,12,13,14,15). Moreover, the Zn uptake system protein ZnuA is required for Brucella virulence (16, 17), and Bru- …”

Section: Importancementioning

confidence: 99%

“…These metal ions have extremely high binding affinities for generic divalent cation binding sites in proteins, and the binding of these cations to inappropriate sites, such as sites requiring Fe or Mn for proper protein function, can inactivate the proteins, leading to toxicity and cell death (6). Thus, it is not surprising that organisms from single-celled bacteria to multicellular mammals have evolved cellular mechanisms to stringently control the uptake, export, utilization, and storage of metal ions.It has been estimated that Ͼ5% of bacterial proteins bind Zn (9), and several Zn-containing proteins that are important for the basic physiology and virulence of Brucella strains have been identified (10,11,12,13,14,15). Moreover, the Zn uptake system protein ZnuA is required for Brucella virulence (16, 17), and Bru- …”

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confidence: 99%

Coordinated Zinc Homeostasis Is Essential for the Wild-Type Virulence of Brucella abortus

et al. 2015

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Metal homeostasis in bacterial cells is a highly regulated process requiring intricately coordinated import and export, as well as precise sensing of intracellular metal concentrations. The uptake of zinc (Zn) has been linked to the virulence of Brucella abortus; however, the capacity of Brucella strains to sense Zn levels and subsequently coordinate Zn homeostasis has not been described. Here, we show that expression of the genes encoding the zinc uptake system ZnuABC is negatively regulated by the Znsensing Fur family transcriptional regulator, Zur, by direct interactions between Zur and the promoter region of znuABC. Moreover, the MerR-type regulator, ZntR, controls the expression of the gene encoding the Zn exporter ZntA by binding directly to its promoter. Deletion of zur or zntR alone did not result in increased zinc toxicity in the corresponding mutants; however, deletion of zntA led to increased sensitivity to Zn but not to other metals, such as Cu and Ni, suggesting that ZntA is a Zn-specific exporter. Strikingly, deletion of zntR resulted in significant attenuation of B. abortus in a mouse model of chronic infection, and subsequent experiments revealed that overexpression of zntA in the zntR mutant is the molecular basis for its decreased virulence. IMPORTANCEThe importance of zinc uptake for Brucella pathogenesis has been demonstrated previously, but to date, there has been no description of how overall zinc homeostasis is maintained and genetically controlled in the brucellae. The present work defines the predominant zinc export system, as well as the key genetic regulators of both zinc uptake and export in Brucella abortus. Moreover, the data show the importance of precise coordination of the zinc homeostasis systems as disregulation of some elements of these systems leads to the attenuation of Brucella virulence in a mouse model. Overall, this study advances our understanding of the essential role of zinc in the pathogenesis of intracellular bacteria.T he pathogenic alphaproteobacterium Brucella abortus preferentially infects cattle, bison, and elk (1), but the bacteria are also highly efficient at infecting humans. In order to establish a chronic infection in these hosts, the brucellae must survive and replicate within host macrophages (2). While the macrophage serves as the niche for Brucella during a chronic infection, the intracellular environment of these phagocytic immune cells is inhospitable as the bacteria are bombarded with a variety of environmental stresses, including exposure to reactive oxygen species (ROS), low pH, limited oxygen availability, and nutrient deprivation (3). Notwithstanding, the brucellae have evolved multiple strategies to cope with the harsh intramacrophagic environment and ultimately establish a replicative niche in these cells.With regard to the nutrient limitation experienced by the brucellae within macrophages, metal cations are likely found in extremely low concentrations, and, in fact, macrophages produce transporters, such as the NRAMP family of transp...

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MucR binds multiple target sites in the promoter of its own gene and is a heat‐stable protein: Is MucR a H‐NS‐like protein?

et al. 2018

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The protein MucR from Brucella spp. is involved in the expression regulation of genes necessary for host interaction and infection. MucR is a member of the Ros/MucR family, which comprises prokaryotic zinc‐finger proteins and includes Ros from Agrobacterium tumefaciens and the Ml proteins from Mesorhizobium loti. MucR from Brucella spp. can regulate the expression of virulence genes and repress its own gene expression. Despite the well‐known role played by MucR in the repression of its own gene, no target sequence has yet been identified in the mucR promoter gene. In this study, we provide the first evidence that MucR from Brucella abortus binds more than one target site in the promoter region of its own gene, suggesting a molecular mechanism by which this protein represses its own expression. Furthermore, a circular dichroism analysis reveals that MucR is a heat‐stable protein. Overall, the results of this study suggest that MucR might resemble a H‐NS protein.

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Brucella melitensis MucR, an Orthologue of Sinorhizobium meliloti MucR, Is Involved in Resistance to Oxidative, Detergent, and Saline Stresses and Cell Envelope Modifications

Cited by 51 publications

References 92 publications

Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

Diverse Genetic Regulon of the Virulence-Associated Transcriptional Regulator MucR in Brucella abortus 2308

Coordinated Zinc Homeostasis Is Essential for the Wild-Type Virulence of Brucella abortus

MucR binds multiple target sites in the promoter of its own gene and is a heat‐stable protein: Is MucR a H‐NS‐like protein?

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