Exit from Competence for Genetic Transformation in Streptococcus pneumoniae Is Regulated at Multiple Levels

Weng, Liming; Piotrowski, Andrew; Morrison, Donald A.

doi:10.1371/journal.pone.0064197

Cited by 57 publications

(79 citation statements)

References 33 publications

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“…Then, once the competence cascade is shut off, cells regain responsiveness to XIP in late-exponential phase, as evinced by the fact that neutralization of the medium or resuspension of cells at an OD of 0.8 in supernatants at an OD of 0.2 or in fresh FMC medium restored the inducibility of comX by XIP. Similar types of circuits that shut off competence in B. subtilis (45) and S. pneumoniae (46,47) have been characterized recently. Evidence for the existence of factors in S. mutans that can control comX expression and impact the ability of ComX to activate comYA and other late com genes has been presented in studies from our laboratory with the rcrRPQ operon (48).…”

Section: Discussionmentioning

confidence: 71%

Growth Phase and pH Influence Peptide Signaling for Competence Development in Streptococcus mutans

Guo

Ahn

Kaspar

et al. 2013

Journal of Bacteriology

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The development of competence by the dental caries pathogen Streptococcus mutans is mediated primarily through the alternative sigma factor ComX (SigX), which is under the control of multiple regulatory systems and activates the expression of genes involved in DNA uptake and recombination. Here we report that the induction of competence and competence gene expression by XIP (sigX-inducing peptide) and CSP (competence-stimulating peptide) is dependent on the growth phase and that environmental pH has a potent effect on the responses to XIP. A dramatic decline in comX and comS expression was observed in midand late-exponential-phase cells. XIP-mediated competence development and responses to XIP were optimal around a neutral pH, although mid-exponential-phase cells remained refractory to XIP treatment, and acidified late-exponential-phase cultures were resistant to killing by high concentrations of XIP. Changes in the expression of the genes for the oligopeptide permease (opp), which appears to be responsible for the internalization of XIP, could not entirely account for the behaviors observed. Interestingly, comS and comX expression was highly induced in response to endogenously overproduced XIP or ComS in mid-exponential-phase cells. In contrast to the effects of pH on XIP, competence induction and responses to CSP in complex medium were not affected by pH, although a decreased response to CSP in cells that had exited early-exponential phase was observed. Collectively, these results indicate that competence development may be highly sensitive to microenvironments within oral biofilms and that XIP and CSP signaling in biofilms could be spatially and temporally heterogeneous.

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Section: Discussionmentioning

confidence: 71%

Growth Phase and pH Influence Peptide Signaling for Competence Development in Streptococcus mutans

Guo

Ahn

Kaspar

et al. 2013

Journal of Bacteriology

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“…The activity and stability of SigX during competence development have been relatively well studied in the model organism S. pneumoniae, which involves a complex regulatory network and multiple components such as ComW, DprA and ClpE/ClpP [28-30,38,39]. However, it was unclear whether the same mechanisms might be used for regulation of the activity and stability of SigX in other members of streptococci that primarily used a ComRS signaling system to control transcription of comX and competence.…”

Section: Discussionmentioning

confidence: 99%

Regulated proteolysis of the alternative sigma factor SigX in Streptococcus mutans: implication in the escape from competence

et al. 2014

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BackgroundSigX (σX), the alternative sigma factor of Streptococcus mutans, is the key regulator for transcriptional activation of late competence genes essential for taking up exogenous DNA. Recent studies reveal that adaptor protein MecA and the protease ClpC act as negative regulators of competence by a mechanism that involves MecA-mediated proteolysis of SigX by the ClpC in S. mutans. However, the molecular detail how MecA and ClpC negatively regulate competence in this species remains to be determined. Here, we provide evidence that adaptor protein MecA targets SigX for degradation by the protease complex ClpC/ClpP when S. mutans is grown in a complex medium.ResultsBy analyzing the cellular levels of SigX, we demonstrate that the synthesis of SigX is transiently induced by competence-stimulating peptide (CSP), but the SigX is rapidly degraded during the escape from competence. A deletion of MecA, ClpC or ClpP results in the cellular accumulation of SigX and a prolonged competence state, while an overexpression of MecA enhances proteolysis of SigX and accelerates the escape from competence. In vitro protein-protein interaction assays confirm that MecA interacts with SigX via its N-terminal domain (NTD1–82) and with ClpC via its C-terminal domain (CTD123–240). Such an interaction mediates the formation of a ternary SigX-MecA-ClpC complex, triggering the ATP-dependent degradation of SigX in the presence of ClpP. A deletion of the N-terminal or C-terminal domain of MecA abolishes its binding to SigX or ClpC. We have also found that MecA-regulated proteolysis of SigX appears to be ineffective when S. mutans is grown in a chemically defined medium (CDM), suggesting the possibility that an unknown mechanism may be involved in negative regulation of MecA-mediated proteolysis of SigX under this condition.ConclusionAdaptor protein MecA in S. mutans plays a crucial role in recognizing and targeting SigX for degradation by the protease ClpC/ClpP. Thus, MecA actually acts as an anti-sigma factor to regulate the stability of SigX during competence development.

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“…In streptococci, competence is a transient physiological bacterial state (Seaton et al, 2011, 2015; Desai et al, 2012; Federle and Morrison, 2012; Guo et al, 2014) and the mechanisms mediating shut-down have only been partially elucidated in some species (Boutry et al, 2012; Tian et al, 2013; Weng et al, 2013; Dong et al, 2014; Wahl et al, 2014). In S. pneumoniae , which possess the ComCDE competence regulatory system, the exit from competence is regulated by multiple ComX dependent- and independent mechanisms (Chastanet et al, 2001; Bergé et al, 2003; Mortier-Barrière et al, 2007; Piotrowski et al, 2009; Martin et al, 2013; Mirouze et al, 2013; Weng et al, 2013) In S. mutans and S. thermophilus which both utilize the ComRS system to regulate competence development, MecA negatively regulates competence development by targeting the ClpC-ClpP protease activity to ComX (Boutry et al, 2012; Tian et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Temporal Regulation of the Transformasome and Competence Development in Streptococcus suis

Zaccaria

Wels²,

Baarlen

et al. 2016

Front. Microbiol.

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In S. suis the ComX-inducing peptide (XIP) pheromone regulates ComR-dependent transcriptional activation of comX (or sigX) the regulator of the late competence regulon. The aims of this study were to identify the ComR-regulated genes and in S. suis using genome-wide transcriptomics and identify their function based on orthology and the construction of specific knockout mutants. The ComX regulon we identified, includes all homologs of the “transformasome” a type 4-like pilus DNA binding and transport apparatus identified in Streptococcus pneumoniae, Streptococcus mutans, and Streptococcus thermophilus. A conserved CIN-box (YTACGAAYW), predicted to be bound by ComX, was found in the promoters of operons encoding genes involved in expression of the transformasome. Mutants lacking the major pilin gene comYC were not transformable demonstrating that the DNA uptake pilus is indeed required for competence development in S. suis. Competence was a transient state with the comX regulon shut down after ~15 min even when transcription of comX had not returned to basal levels, indicating other mechanisms control the exit from competence. The ComX regulon also included genes involved in DNA repair including cinA which we showed to be required for high efficiency transformation. In contrast to S. pneumoniae and S. mutans the ComX regulon of S. suis did not include endA which converts the transforming DNA into ssDNA, or ssbA, which protects the transforming ssDNA from degradation. EndA appeared to be essential in S. suis so we could not generate mutants and confirm its role in DNA transformation. Finally, we identified a putative homolog of fratricin, and a putative bacteriocin gene cluster, that were also part of the CIN-box regulon and thus may play a role in DNA release from non-competent cells, enabling gene transfer between S. suis pherotypes or S. suis and other species. S. suis mutants of oppA, the binding subunit of the general oligopeptide transporter were not transformable, suggesting that it is required for the import of XIP.

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Exit from Competence for Genetic Transformation in Streptococcus pneumoniae Is Regulated at Multiple Levels

Cited by 57 publications

References 33 publications

Growth Phase and pH Influence Peptide Signaling for Competence Development in Streptococcus mutans

Growth Phase and pH Influence Peptide Signaling for Competence Development in Streptococcus mutans

Regulated proteolysis of the alternative sigma factor SigX in Streptococcus mutans: implication in the escape from competence

Temporal Regulation of the Transformasome and Competence Development in Streptococcus suis

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