A role for the DtxR family of metalloregulators in gram-positive pathogenesis

Merchant, Anjali T.; Spatafora, Grace A.

doi:10.1111/mom.12039

Cited by 6 publications

(8 citation statements)

References 14 publications

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“…In many cases, the genes under positive control are associated with binding sites for the metalloregulator (as defined through bioinformatics, biochemical assays, or in vivo results), but whether or not transcriptional activation is direct or indirect is generally not resolved. Our results support the notion that the central role of MntR in coordinating Mn(II) homeostasis (Merchant and Spatafora, 2014) can include direct regulation of both uptake and efflux.…”

Section: Discussionsupporting

confidence: 87%

“…MntR is a Mn(II) specific transcriptional regulator structurally related to the DtxR/IdeR family of iron sensors (Boyd et al, 1990;Glasfeld et al, 2003;. Members of this large and diverse protein family function to sense Fe, Mn, or both, and are key regulators in several pathogens (Merchant and Spatafora, 2014). An mntR null mutant is extremely sensitive to Mn(II) intoxication.…”

Section: Introductionmentioning

confidence: 99%

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Bacillus subtilis MntR coordinates the transcriptional regulation of manganese uptake and efflux systems

Huang

Shin

Pinochet-Barros

et al. 2016

Molecular Microbiology

104

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Summary The Bacillus subtilis MntR metalloregulatory protein senses manganese, an essential element required for central metabolism, oxidative stress resistance and replication. An mntR null mutant is highly sensitive to Mn(II) intoxication, which is attributed in part to the constitutive expression of two importers: the proton-dependent NRAMP family transporter MntH and the ABC transporter MntABCD. Here, we show that an mntR null mutant is still sensitive to Mn(II) intoxication even if both of the import systems are absent. This Mn(II) sensitivity results from the requirement for MntR to activate the transcription of two genes encoding cation diffusion facilitator (CDF) family efflux pumps. Physiological studies indicate that MneP (formerly YdfM) serves as the primary Mn(II) efflux pump with MneS (formerly YeaB) playing a secondary role. Mutant strains lacking mneP are Mn(II) sensitive and accumulate elevated levels of Mn(II), and these effects are exacerbated in a mneP mneS double mutant. DNA-binding and in vitro transcription studies demonstrate that MntR binds to both the mneP and mneS regulatory regions and directly activates transcription in response to levels of Mn(II) several-fold higher than required for repression of import genes. These results highlight the delicate balance of Mn(II) uptake and efflux systems controlled by MntR.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Bacillus subtilis MntR coordinates the transcriptional regulation of manganese uptake and efflux systems

Huang

Shin

Pinochet-Barros

et al. 2016

Molecular Microbiology

104

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“…Members of this large and diverse protein family function to sense iron, manganese, or both, and are key regulators in several pathogens (53). B. subtilis MntR represses two manganese uptake systems: the ATP-dependent MntABCD transporter and MntH, a protoncoupled symporter (54).…”

Section: The Mntr Regulon and Manganese Homeostasismentioning

confidence: 99%

Specificity of Metal Sensing: Iron and Manganese Homeostasis in Bacillus subtilis

Helmann

2014

Journal of Biological Chemistry

129

127

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Metalloregulatory proteins allow cells to sense metal ions and appropriately adjust the expression of metal uptake, storage, and efflux pathways. Bacillus subtilis provides a model for the coordinate regulation of iron and manganese homeostasis that involves three key regulators: Fur senses iron sufficiency, MntR senses manganese sufficiency, and PerR senses the intracellular Fe/Mn ratio. Here, I review the structural and physiological bases of selective metal perception, the effects of non-cognate metals, and mechanisms that may serve to coordinate iron and manganese homeostasis. Manganese and Iron: Chemically Similar Elements with Distinct Roles in Cell PhysiologyManganese and iron are both predominantly present as divalent cations in the reducing environment of the cytoplasm and are maintained at overall concentrations (averaged over the cell) that can approach 0.5 mM (1-3). Much of this manganese and iron is bound by enzymes that acquire metal from a kinetically accessible (labile) pool buffered in the low M range (4 -6). These two metals are not only important from the perspective of individual microbial cells, but have a global impact due to their central roles in photosynthesis, nitrogen fixation, and other key steps in elemental cycling.Nearly all cellular life requires significant amounts of iron. The sole documented exceptions are the lactobacilli and the spirochete Borrelia burgdorferi, which have little if any requirement for iron (3). Coincident with this disregard for iron, these same organisms have high requirements for manganese and have been described as manganese-centric (7). Conversely, other organisms have little demonstrable requirement for manganese, although they may use manganese when available. The best characterized is Escherichia coli, which has a largely ironcentric metabolism, but conditionally imports manganese in response to oxidative stress (8).Here, I review the key factors regulating iron and Mn homeostasis in the model organism Bacillus subtilis. B. subtilis encodes three members of the Fur 2 family (Fur, PerR, and Zur) and one member of the DtxR/MntR family (MntR) that regulate the import of nutrient metal ions (9 -11). Structural and biochemical studies have provided insights into the mechanisms of selective activation of these repressors by their cognate metal ions (12-14). B. subtilis requires both iron and manganese for growth, a property shared with many pathogens for which the ability to obtain these metals from the host is a critical determinant of virulence (7,(15)(16)(17). Metalloregulators as a Window into Cellular PhysiologyMetalloregulators function as the arbiters of metal ion sufficiency and excess (6,12,18). For those that sense sufficiency, the affinity (measured as K d ) for their cognate metal(s) defines the level of metal judged to be sufficient. When free metal concentrations rise above this level, the regulator transitions from its inactive (apo-) form to its activated (holo-) form and represses expression of metal import. In B. subtilis, Fur serves as ...

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“…There are three main classes of transcriptional regulators of Mn import systems: (i) dedicated Mn-binding transcriptional repressors, (ii) Fe-binding transcriptional repressors, and (iii) regulators that sense oxidative stress. For more information on the structure and function of Mn-metalloregulators and Fur-Mn interactions, we point the reader to recent reviews (Lisher and Giedroc, 2013;Troxell and Yang, 2013;Helmann, 2014;Merchant and Spatafora, 2014).…”

Section: Bacterial Regulation Of the Mn-restriction Responsementioning

confidence: 99%

“…Mn-binding metalloregulators prototypically fall either into the MntR family (Merchant and Spatafora, 2014) or the Mur family (Lee and Helmann, 2007). Both MntR and Mur function by binding to specific sequences in the promoters of their regulated genes and blocking transcription; this only occurs when the regulatory protein is bound to Mn, which induces a conformational change permissive to DNA binding (Schmitt, 2002;Guedon et al, 2003;Kliegman et al, 2006).…”

Section: Bacterial Regulation Of the Mn-restriction Responsementioning

confidence: 99%

Manganese homeostasis and utilization in pathogenic bacteria

Juttukonda

Skaar

2015

Molecular Microbiology

102

129

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Summary Manganese is a required cofactor for all forms of life. Given the importance of Mn to bacteria, the host has devised strategies to sequester Mn from invaders. In the macrophage phagosome, NRAMP1 removes Mn and other essential metals to starve intracellular pathogens; in the extracellular space, calprotectin chelates Mn and Zn. Calprotectin-mediated Mn sequestration is a newly appreciated host defense mechanism and recent findings are highlighted herein. In order to acquire Mn when extracellular concentrations are low, bacteria have evolved efficient Mn acquisition systems that are under elegant transcriptional control. To counteract Mn overload, some bacteria possess Mn-specific export systems which are important in vivo, presumably for control of intracellular Mn levels. Mn transporters, their transcriptional regulators, and some Mn-requiring enzymes are necessary for virulence of certain bacterial pathogens, as revealed by animal models of infection. Furthermore, Mn is an important facet of the cellular response to oxidative stress, a host antibacterial strategy. The battle for Mn between host and pathogen is now appreciated to be a major determinant of the outcome of infection. In this MicroReview, the contribution of Mn to the host-pathogen interaction is reviewed and key questions are proposed for future study.

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A role for the DtxR family of metalloregulators in gram-positive pathogenesis

Cited by 6 publications

References 14 publications

Bacillus subtilis MntR coordinates the transcriptional regulation of manganese uptake and efflux systems

Bacillus subtilis MntR coordinates the transcriptional regulation of manganese uptake and efflux systems

Specificity of Metal Sensing: Iron and Manganese Homeostasis in Bacillus subtilis

Manganese homeostasis and utilization in pathogenic bacteria

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