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Regulation of Bacterial MntH Genes

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Bacterial NRAMP-like transporters, generically referred to as MntH proteins, appear to function primarily as Mn(II) uptake systems induced under conditions of manganese limitation. Regulation of mntH gene expression usually involves a Mn(II)-sensing regulatory protein, MntR. In the enteric bacteria, regulation additionally involves the iron-sensing Fur regulatory protein and the peroxide-sensing OxyR activator. This complex regulation is indicative of the fact that Mn(II) is important not only for its role as an enzyme cofactor, but also for its ability to help detoxify reactive oxygen species.

Introduction

All organisms require numerous metal ions for growth. Metal ion influx and efflux are mediated by a combination of ATP- and proton-dependent mechanisms.1,2 The metal ion transporters found in eukaryotic cells are often closely related to their prokaryotic orthologs. For example, the copper transporters implicated in both Menkes' and Wilson's diseases bear striking similarity to ATP-dependent efflux pumps important for copper resistance in Bacteria.3,4

The Natural Resistance-Associated Macrophage Protein (NRAMP) family of eukaryotic transporters was identified based on the effect of these proteins on the multiplication of intracellular pathogens.5 Bacterial genes encoding members of the NRAMP family of transporters were initially identified based on sequence similarity with their eukaryotic counterparts.6,7 Where the functional role of these NRAMP-type transporters has been documented (in Mycobacterium tuberculosis, Bacillus subtilis, Escherichia coli, and Salmonella enterica) the weight of the available evidence suggests a primary role in the uptake of Mn(II) ion.810 The name MntH (Manganese transport, H-dependent) was therefore adopted for this bacterial protein family. However, a role in the transport of other metal ions in these or other bacteria cannot be rigorously excluded. Additional uncharacterized homologs are present in most sequenced bacterial genomes. In this chapter we will focus specifically on the regulatory pathways governing the expression of NRAMP-like (MntH) transporters in bacterial systems.

Despite the similarities between bacterial and eukaryotic transport machinery, the regulatory pathways that control the expression of metal ion homeostasis systems are completely distinct.1,2,11 In eukaryotic cells, metal ion uptake functions are often controlled by metal-sensing transcription activators such as the yeast iron sensor AFT1,12 the zinc sensor ZAP1,13 or the MRE-binding protein in human cells.14,15 In the case of iron homeostasis genes, translational control mediated by IRE-binding proteins plays a prominent role.16 In bacterial systems, metal homeostasis is most frequently controlled by metal-sensing repressors such as Fur (ferric uptake repressor), Zur (zinc uptake repressor), or MntR (manganese transport regulator).17 Efflux systems may be controlled by either metal-sensitive repressors, such as the zinc sensor SmtB, or by transcription activators of the MerR family.18,19 Regulation of mntH genes in response to Mn(II) is mediated primarily by MntR. In the enteric bacteria, additional regulation involves the Fe(II)-sensing Fur protein and the peroxide-sensing OxyR factor.

Mycobacterium tuberculosis

One of the first bacterial NRAMP homologs to attract attention was the M. tuberculosis homolog, for which the designation MRAMP was proposed.20 The function of this hypothetical transporter was investigated by microinjection of the corresponding mRNA into Xenopus oocytes. In this context, the MRAMP transporter mediates uptake of divalent zinc and iron, with competitive inhibition noted for both manganese and copper.20 The authors conclude that this transporter interacts with a range of divalent cations. The regulation of MRAMP was investigated in M. tuberculosis using RT-PCR. The results indicate that MRAMP is up-regulated when cells are grown in the presence of high concentrations of Fe(II) or Cu(II).20 Since transporters that function to import metal ions are usually repressed rather than induced by their substrates, this result is surprising. It should be noted, however, that the levels of Fe(II) and Cu(II) used in this study were sufficient to inhibit bacterial growth. It is therefore plausible that these ions act as competitive inhibitors of the transport of another essential ion, perhaps Mn(II), mediated by the MRAMP protein. Recent results indicate that MntH is not a virulence determinant for M. tuberculosis.21,22 The lack of a significant role for MntH in growth, either in vitro or in the mammalian host, is likely indicative of a redundancy of transport systems for metal ion acquisition.

Bacillus subtilis

One of the first clues to suggest a major role for bacterial NRAMPs in Mn(II) uptake emerged from genetic analysis of metal-regulated gene expression in B. subtilis.10 This Gram positive bacterium encodes a homolog of the well characterized diphtheria toxin repressor (DtxR) protein of Corynebacterium diphtheriae. In C. diphtheriae, DtxR senses Fe(II) and regulates the expression of both diphtheria toxin and iron homeostasis genes.23

Unlike DtxR, which senses Fe(II), the B. subtilis DtxR homolog is a Mn(II)-specific regulator designated MntR.10 Wild-type B. subtilis requires low levels (usually nanomolar) of manganese for growth and can tolerate up to 1 mM. When an mntR null mutant was constructed the resulting cells were extremely sensitive to Mn(II), presumably because of an inability of the cells to shut-off the expression of transporters.10 The mntR mutant strain can not grow at concentrations of Mn(II) above 5 μM. The sensitivity of the mntR mutant to several other tested metal ions was unaffected. These results led us to speculate that the function of MntR was to regulate one or more transporters that act to import Mn(II).

The extreme Mn(II) sensitivity of the B. subtilis mntR mutant strain provides a powerful genetic selection for suppressor mutations. A major class of transposon-generated suppressor mutations were insertions in a gene encoding an NRAMP homolog, subsequently designated MntH (Manganese transport, H-dependent). Using reporter fusions it was demonstrated that mntH transcription is induced by growth under Mn(II) limiting conditions. Expression can be repressed by Mn(II), but by none of the other divalent metal ions tested.10 These results are consistent with the idea that uptake of Mn(II) is the major physiological function of MntH.

To identify other genes that are controlled by MntR, the operator sites required for regulation of MntH were characterized. MntR binds to at least three sites in the mntH promoter region as judged by electrophoretic mobility shift assays and DNase I footprinting. The core region required for binding has similarity to other operator elements regulating known or putative Mn(II) uptake systems in other bacteria (Table 1). When the mntH operator was used to search the B. subtilis genome for related elements, the closest match was to a region just upstream of the ytgABCD operon (renamed mntABCD) encoding a putative Mn(II)-selective ABC transporter. Both the MntH (proton-dependent) and MntABCD (ATP-dependent) transporters are repressed by Mn(II) with comparable sensitivity: repression is complete when the medium contains >1 μM Mn(II).10 The regulation of these operons by Mn(II) clearly requires MntR, but the mechanistic details have only recently become clear.

Table 1. Recognition sites for the manganese transport regulator, MntR.

Table 1

Recognition sites for the manganese transport regulator, MntR.

Based on initial studies, using reporter fusions, we proposed that MntR was a dual function regulator: MntR acted to induce expression of the mntABCD operon under Mn(II)-limiting conditions and to repress mntH when Mn(II) is in excess.10 However, this model has been revised in light of recent RNA-based measurements (including DNA microarrays and slot blot analyses) that indicate that both operons are targets of MntR-mediated repression (our unpublished data). This discrepancy resulted from our analysis of mntA transcription using a transcriptional fusion of the mntA promoter region. This PmntA-lacZ operon fusion is not expressed in mntR mutant strains.10 However, this is due to instability of this particular mRNA in this genetic background. This experience serves as a reminder that it is important to verify effects detected using reporter fusions with direct, RNA-based measurements.

Our current model for MntR regulation states that MntR represses both mntH and mntABCD in response to Mn(II), but not to other metal ions (Fig. 1A). Of particular interest, neither mntH nor mntABCD were identified as part of the Fur regulon, and neither is repressed in response to iron.24 This contrasts with recent findings in the enteric bacteria.25 The Mn(II) selectivity of transcriptional control is in agreement with measurements of metal ion transport in wild-type and various mutant strains of B. subtilis which establish that MntH has a primary role in the uptake of Mn(II) (M. Cellier, personal communication).

Figure 1. Regulation of Bacterial NRAMP (MntH) Genes.

Figure 1

Regulation of Bacterial NRAMP (MntH) Genes. A) The B. subtilis mntH gene is repressed by MntR binding to an extended operator region (dashed line; from approximately -15 to +53 relative to the transcription start site) overlapping the promoter (P). The (more...)

Staphylococcus aureus

Recent results demonstrate that the manganese homeostasis circuitry in S. aureus is mediated by transporters similar to those described in B. subtilis.26,27 In both organisms, MntR acts as a manganese-dependent regulator of Mn(II) uptake systems, but the role of MntR in regulation of S. aureus mntH appears complex.

The MntABC system is critical for achieving high cell densities in media containing sub-micromolar levels of Mn(II), suggesting that this is the higher affinity transport system.26 Repression of the mntABC operon is highly selective for Mn(II) and is unaffected by other tested metal ions. This repression requires MntR. Thus, at this promoter, MntR behaves as a Mn(II) dependent repressor, just as it does for both mntABCD and mntH in B. subtilis.

In contrast, expression of mntH is reduced about 2- to 4-fold in an mntR mutant and does not appear to be regulated by Mn(II).26 This is a surprising result, but seems to suggest that MntR might act as a positive regulator of mntH (Fig. 1B). This is similar to our original (but erroneous) suggestion that MntR functioned as a positive regulator of mntABCD in B. subtilis. The lack of regulation of S. aureus mntH by Mn(II) is unexpected, and raises the possibility that this protein may in fact transport another metal ion or transport Mn(II) in response to a physiological stimulus distinct from metal ion starvation. It is interesting to note, for example, that B. subtilis contains a Zn(II) uptake system that is not regulated by Zn(II), but is induced under conditions of peroxide stress to import Zn(II) as an antioxidant.28 It is possible that in S. aureus MntH may be regulated by signals other than metal ion starvation, such as oxidative stress. Alternatively, the lack of Mn(II) regulation may be related to the fact that S. aureus mntH is phylogenetically distinct from the B. subtilis ortholog, belonging instead to a sub-family of bacterial mntH genes that may have been acquired by lateral gene transfer from eukaryotes.29

Escherichia coli and Salmonella enterica serovar Typhimurium

The MntH orthologs in the enterobacteria were described by both the Cellier and Maguire laboratories as proton-dependent transporters with a primary role in the uptake of Mn(II).8,9 The mntH locus is subject to complex regulation in response to manganese, iron, and reactive oxygen species (Fig. 1C). In an initial characterization of mntH regulation in S. enterica serovar Typhimurium using an mntH::lacZYA reporter system, Kehres et al reported a strong transcriptional induction after treatment with EDTA or hydrogen peroxide, but little if any induction by the superoxide generator, paraquat.8 Analysis of the promoter and regulatory regions of mntH from S. enterica serovar Typhimurium led these authors to speculate that mntH was under the control of the metal-sensing Fur and peroxide-sensing OxyR proteins. Since Fur protein can respond to either Fe(II) or Mn(II), at least at some promoter sites, the authors speculated that Fur might mediate both types of regulation: a model refined in subsequent studies.

Patzer and Hantke reported the first detailed analysis of mntH regulation in E. coli.30 Their results demonstrate that mntH is regulated by an MntR repressor similar to that found in B. subtilis, as well as by Fur. They initially identified a mntH::Mud-lac insertion in a random screen for genes repressed by iron and induced by the iron chelator, 2,2'-dipyridyl: the hallmarks of Fur-regulated genes.30 Significantly, they found that either iron or manganese could elicit repression with an additional weaker effect noted for cobalt. The ability of iron to elicit repression was abolished in a fur mutant strain, but manganese repression was Fur-independent. Therefore, they used random mutagenesis to identify mutants derepressed for mntH expression on plates containing Mn(II). The resulting derepressed mutants were complemented by plasmids encoding MntR, an ortholog of the Mn(II)-sensing repressor from B. subtilis. Thus, Patzer and Hantke concluded that mntH is under the dual control of Fur, mediating iron repression, and MntR, mediating manganese repression.30

This model of regulaton has been refined by Kehres et al based on studies of mntH regulation in S. enterica serovar Typhimurium.25 These authors demonstrate that the mntH regulatory region in S. enterica serovar Typhimurium (and by homology, that in other enterobacteria) contains a σ70 promoter element with three closely linked regulator binding sites (Fig. 1C). Just upstream of the -35 promoter element is an OxyR binding site required for peroxide-induction. A Fur box motif required for iron-mediated repression overlaps the -35 element while the MntR-binding motif identified by Patzer and Hantke overlaps the transcription start site. In agreement with previous results,30 Kehres et al find that mntH expression is repressed by either Mn(II) or Fe(II) at 10 μM with a slight effect of Co(II) noted at 10-fold higher levels.25

To dissect the roles of the various regulatory proteins in mediating repression, Kehres et al introduced mutations in the regulators, in the regulator-binding sites (cis-acting elements), or both.25 The results were unexpectedly complex. The data indicate that mntH repression by iron is only partially eliminated by mutation of either the fur protein, the Fur box motif, or both (In contrast, the effects of cobalt were entirely Fur-dependent). The residual iron-regulation was lost in double mutant strains in which both the Fur- and MntR-regulatory systems are disrupted. Thus, E. coli MntR, unlike the B. subtilis ortholog, can apparently respond to micromolar levels of iron. It should be noted that the ability of MntR to respond to iron in the fur mutant strain is not necessarily physiological, since fur mutants are derepressed for iron uptake and therefore have elevated intracellular iron levels. However, this objection is obviated by experiments in which the Fur regulatory system is intact, and thus iron homeostasis is expected to be normal, and only the Fur box element is mutated. In this strain there is still significant, MntR-dependent, repression of mntH by iron.25

Analysis of the manganese effects on mntH transcription was equally complex. Transcription of mntH is sensitive to sub-micromolar levels of Mn(II) added to the medium, and this repression is unaffected by mutation of either fur or the Fur box motif. However, significant manganese repression was still observed in an mntR mutant strain. This residual manganese regulation was eliminated in the fur mntR double mutant.25 Thus, Fur can sense Mn(II) to regulate this promoter, at least in an mntR mutant background in which Mn(II) uptake is derepressed. Since elimination of the mntR-binding motif by itself abolished manganese-dependent regulation, it was not possible to investigate the ability of Fur to sense Mn(II) in an otherwise wild-type background. Moreover, this result suggests that the ability of manganese-liganded Fur to repress mntH requires DNA sequences overlapping the MntR-binding motif. In contrast, the iron-liganded Fur protein requires a classical Fur box to repress transcription.

The complexity of regulation of mntH seen in S. enterica illustrates that many metalloregulators can respond to more than one metal ion in vivo. Indeed, Fur is known to respond to Mn(II) at other sites.31 It has been argued that the ability of high concentrations of Mn(II) to repress iron uptake functions may be one of the mechanisms leading to Mn(II) toxicity: selection for Mn(II) resistant bacteria frequently leads to the isolation of fur mutants. 32 Similarly, the ability of S. enterica MntR to respond to Fe(II) in addition to Mn(II) is reminiscent of SirR, an MntR-like regulator of Staphylococcus epidermidis that responds to both metal ions.33

The final aspect of mntH regulation is the peroxide-induction mediated by OxyR. Transcription of mntH can be strongly induced by hydrogen peroxide and this induction can overcome the iron- or manganese-mediated inhibition noted above.25 The significance of mntH induction by hydrogen peroxide is unclear, but it is likely related to the observation that mntH mutants have an increased susceptibility to peroxide-mediated killing in S. enterica. It is reasonable to suggest that increased Mn(II) uptake under oxidative stress conditions serves a protective role in the cell. Mn(II) is known to play a major role in protecting bacteria against superoxide stress.3438 While mntH expression is not peroxide-inducible in B. subtilis, this organism has another dedicated metal uptake system that responds to peroxide stress: the ZosA protein is a Zn(II) uptake P-type ATPase that is specifically induced by hydrogen peroxide as part of the PerR regulon.28 ZosA is postulated to protect cells against peroxide-stress by displacing iron, copper, and other redox active metal ions from adventitious binding sites in the cell where Fenton chemistry can lead to cell damage. In the Enterobacteriaceae, manganese uptake may play a similar role.27,35

In summary, these studies establish that mntH regulation in S. enterica involves a complex interplay between at least three regulatory circuits. The presence of similar regulatory sites in the corresponding DNA sequences from S. enterica ssp. typhi and Yersinia pestis suggests that other members of the Enterobacteriaceae may have similarly complex mntH regulation. In contrast, regulation in B. subtilis seems quite simple, with MntR being the only regulator so far documented as directly affecting mntH transcription. Further studies will be necessary to clarify the regulators that affect mntH expression in S. aureus, M. tuberculosis, and the many other bacteria that clearly harbor orthologues.

Acknowledgements

Work in our laboratory on MntR and metalloregulation is supported by the National Institutes of Health (GM59323).

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