MtsR is a dual regulator that controls virulence genes and metabolic functions in addition to metal homeostasis in the group A streptococcus

Toukoki, Chadia; Gold, Kathryn M.; McIver, Kevin S.; Eichenbaum, Zehava

doi:10.1111/j.1365-2958.2010.07157.x

Cited by 38 publications

(43 citation statements)

References 70 publications

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“…This organization is reminiscent of the 46-bp ScaR target sequence in S. gordonii, which includes two palindromic elements that straddle the scaC promoter (24). In fact, similar repeat sequences and promoter structures appear to be conserved in the control regions of the fim, psa, and mts operons across several streptococcal species (23)(24)(25)(26)(27)(28), suggesting that they may share similar binding mechanisms with sloA.…”

Section: Discussionmentioning

confidence: 94%

“…S1 in the supplemental material). Although a 42-bp SloR footprint seems large compared with that of C. diphtheria DtxR, which protects 33 bp through the action of two overlapping dimers (11), it is not unlike that of the MtsR metalloregulator in group A streptococci, which protects a 62-bp region of DNA, and that of the ScaR regulator in S. gordonii, which protects a 46-bp region (23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…SloR belongs to a group of metalloregulators from streptococcal species that share substantial sequence identity: ScaR from Streptococcus gordonii, PsaR from Streptococcus pneumoniae, and MtsR from Streptococcus pyogenes are 62%, 58%, and 57% identical in sequence to SloR, respectively (23,25,28). Each of these proteins has been previously characterized, and, in the case of ScaR, X-ray crystal structures of the metal-free and the Zn 2ϩ -or Cd 2ϩ -bound forms have been reported (23).…”

Section: Discussionmentioning

confidence: 99%

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Interactions of the Metalloregulatory Protein SloR from Streptococcus mutans with Its Metal Ion Effectors and DNA Binding Site

et al. 2015

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Streptococcus mutans is the causative agent of dental caries, a significant concern for human health, and therefore an attractive target for therapeutics development. Previous work in our laboratory has identified a homodimeric, manganese-dependent repressor protein, SloR, as an important regulator of cariogenesis and has used site-directed mutagenesis to map functions to specific regions of the protein. Here we extend those studies to better understand the structural interaction between SloR and its operator and its effector metal ions. The results of DNase I assays indicate that SloR protects a 42-bp region of DNA that overlaps the sloABC promoter on the S. mutans UA159 chromosome, while electrophoretic mobility shift and solution binding assays indicate that each of two SloR dimers binds to this region. Real-time semiquantitative reverse transcriptase PCR (real-time semiqRT-PCR) experiments were used to determine the individual base pairs that contribute to SloR-DNA binding specificity. Solution studies indicate that Mn 2؉ is better than Zn 2؉ at specifically activating SloR to bind DNA, and yet the 2.8-Å resolved crystal structure of SloR bound to Zn 2؉ provides insight into the means by which selective activation by Mn 2؉ may be achieved and into how SloR may form specific interactions with its operator. Taken together, these experimental observations are significant because they can inform rational drug design aimed at alleviating and/or preventing S. mutans-induced caries formation. IMPORTANCE This report focuses on investigating the SloR protein as a regulator of essential metal ion transport and virulence gene expression in the oral pathogen Streptococcus mutans and on revealing the details of SloR binding to its metal ion effectors and binding to DNA that together facilitate this expression. We used molecular and biochemical approaches to characterize the interaction of SloR with Mn2؉ and with its SloR recognition element to gain a clearer picture of the regulatory networks that optimize SloRmediated metal ion homeostasis and virulence gene expression in S. mutans. These experiments can have a significant impact on caries treatment and/or prevention by revealing the S. mutans SloR-DNA binding interface as an appropriate target for the development of novel therapeutic interventions. Cariogenesis is a disease that derives from interactions involving the human dentition, an acidogenic microflora, including Streptococcus mutans, and dietary factors. Specifically, S. mutans, which is among the most cariogenic of the oral microbes, assumes an obligate biofilm lifestyle upon colonizing the tooth surface during the first year of life, shortly after tooth eruption. Commonly found in the human oral cavity as the most abundant species in the dental plaque biofilm, S. mutans metabolizes exogenous dietary carbohydrates to generate energy for itself via fermentation and releases acid as a metabolic byproduct. The buffering capacity of saliva combined with appropriate oral hygiene practices can maintain the p...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interactions of the Metalloregulatory Protein SloR from Streptococcus mutans with Its Metal Ion Effectors and DNA Binding Site

et al. 2015

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“…The homologous regulator MtsR of S. pyogenes also controls a large regulon that includes the genes encoding the Mn 2ϩ and Fe 2ϩ transporter MtsABC (90,91). MtsR also represses the dnaK operon, suggesting that it mediates the response of dnaK to heat shock (90).…”

Section: One-component Systemsmentioning

confidence: 99%

Stress Physiology of Lactic Acid Bacteria

Papadimitriou

Alegría

Bron

et al. 2016

Microbiol Mol Biol Rev

515

404

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SUMMARYLactic acid bacteria (LAB) are important starter, commensal, or pathogenic microorganisms. The stress physiology of LAB has been studied in depth for over 2 decades, fueled mostly by the technological implications of LAB robustness in the food industry. Survival of probiotic LAB in the host and the potential relatedness of LAB virulence to their stress resilience have intensified interest in the field. Thus, a wealth of information concerning stress responses exists today for strains as diverse as starter (e.g.,Lactococcus lactis), probiotic (e.g., severalLactobacillusspp.), and pathogenic (e.g.,EnterococcusandStreptococcusspp.) LAB. Here we present the state of the art for LAB stress behavior. We describe the multitude of stresses that LAB are confronted with, and we present the experimental context used to study the stress responses of LAB, focusing on adaptation, habituation, and cross-protection as well as on self-induced multistress resistance in stationary phase, biofilms, and dormancy. We also consider stress responses at the population and single-cell levels. Subsequently, we concentrate on the stress defense mechanisms that have been reported to date, grouping them according to their direct participation in preserving cell energy, defending macromolecules, and protecting the cell envelope. Stress-induced responses of probiotic LAB and commensal/pathogenic LAB are highlighted separately due to the complexity of the peculiar multistress conditions to which these bacteria are subjected in their hosts. Induction of prophages under environmental stresses is then discussed. Finally, we present systems-based strategies to characterize the “stressome” of LAB and to engineer new food-related and probiotic LAB with improved stress tolerance.

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“…Although the conserved Rgg binding site is highly conserved in the two shp promoters, the remainder of the intergenic regions between each shp and rgg gene is highly divergent (10) and could support differential regulation by other regulatory proteins. There is evidence supporting this idea, at least in part, as the metaldependent regulator MtsR is known to regulate the shp3 promoter but is not known to have any role in shp2 regulation (30). Taking this idea farther, if regulatory inputs are indeed distinct at the two shp promoters, it may be that shp2 is in fact sufficient to support autoinduction under specific, yet-to-be determined conditions despite not having sufficient activity under the growth conditions used for these studies.…”

Section: Discussionmentioning

confidence: 99%

Redundant Group A Streptococcus Signaling Peptides Exhibit Unique Activation Potentials

LaSarre

Chang

Federle

2013

Journal of Bacteriology

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All bacterial quorum sensing (QS) systems are based on the production, secretion, and detection of small signaling molecules. Gram-positive bacteria typically use small peptides as QS effectors, and each QS circuit generally requires the interaction of a single signaling molecule with a single receptor protein. The recently described Rgg2 and Rgg3 (Rgg2/3) regulatory circuit of Streptococcus pyogenes (group A streptococcus [GAS]) is one of only a few QS circuits known to utilize multiple signaling peptides. In this system, two distinct, endogenously produced peptide pheromones (SHP2 and SHP3) both function to activate the QS circuit. The aim of this study was to further define the roles of SHP2 and SHP3 in activation of the Rgg2/3 QS system, specifically with regard to shp gene identity and dosage. Results from our studies using transcriptional reporters and isogenic GAS mutants demonstrate that shp gene dosage does contribute to Rgg2/3 system induction, as decreased gene dosage results in decreased or absent induction. Beyond this, however, data indicate that the shp genes possess distinct potentials for supporting system activation, with shp3 more readily able to support system activation than shp2. Studies using synthetic peptides and shp gene mutants indicate that the disparate activities of endogenous SHPs are due to production, rather than signaling, differences and are conferred by the N-terminal regions rather than the C-terminal signaling regions of the peptides. These data provide evidence that the N-terminal, noneffector sequences of SHP pheromones influence their production efficiencies and thereby the relative activation potentials of endogenous SHPs.

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MtsR is a dual regulator that controls virulence genes and metabolic functions in addition to metal homeostasis in the group A streptococcus

Cited by 38 publications

References 70 publications

Interactions of the Metalloregulatory Protein SloR from Streptococcus mutans with Its Metal Ion Effectors and DNA Binding Site

Interactions of the Metalloregulatory Protein SloR from Streptococcus mutans with Its Metal Ion Effectors and DNA Binding Site

Stress Physiology of Lactic Acid Bacteria

Redundant Group A Streptococcus Signaling Peptides Exhibit Unique Activation Potentials

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