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Molecular Microbiology (2010) 78(3), 541–544 䊏 doi:10.1111/j.1365-2958.2010.07380.x First published online 27 September 2010 MicroCommentary Increasing competence in the genus Streptococcus mmi_7380 541..544 Leiv Sigve Håvarstein* Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, N-1432 Ås, Norway. Summary Streptococcus pneumoniae is one of the most important model organisms for studies on natural genetic transformation in bacteria. The prevalence of this gene exchange mechanism in the genus Streptococcus has not been subjected to systematic investigations, but it has been known for decades that only a few streptococcal species develop the competent state spontaneously when grown under laboratory conditions. The recent discovery of a new mechanism regulating natural transformation in Streptococcus thermophilus suggested that this property might be more widespread among streptococci than previously thought. This suspicion has been confirmed by Mashburn-Warren and co-workers, who in the current issue of Molecular Microbiology report the discovery of a novel competence-inducing pheromone that is conserved in Streptococcus mutans and a number of pyogenic streptococci. Comparative analyses of bacterial genomes have shown that horizontal gene transfer (HGT) is widespread in the bacterial domain of life. HGT is a major driving force of evolution that sometimes gives rise to quantum evolutionary leaps that increase bacterial fitness and their capacity to colonize new ecological niches. There are three recognized HGT mechanisms operating in bacteria: transduction, conjugation and natural genetic transformation. At present, it is not known which of these is the most important, i.e. contributes most to the total exchange of genetic material between microbes in nature. Natural transformation has been considered the least prevalent and perhaps the least important of the three HGT mechanisms. Whereas most bacteria are able to exchange genetic information by conjugation and transduction, only about Accepted 26 August, 2010. *For correspondence. E-mail sigve. [email protected]; Tel. (+47) 64965883; Fax (+47) 64965901. © 2010 Blackwell Publishing Ltd 65 bacterial species have so far been documented to be naturally transformable (Johnsborg et al., 2007). Nevertheless, natural transformation is of special interest because it represents the only form of HGT that is initiated and fully controlled by the cell taking up foreign genetic material. In contrast to conjugation and transduction, which depend on mobile genetic elements such as plasmids, transposons and bacteriophages, natural transformation is part of the normal physiology of the competent bacterium. Consequently, natural transformation must be considered as genuine bacterial ‘sex’. Furthermore, as the mechanism is conserved in members of at least six different bacterial phyla, it is probably very old in evolutionary terms (Johnsborg et al., 2007). Natural transformation was first observed by Frederick Griffith in 1928 (Griffith, 1928) when he studied the conditions responsible for acquisition of a capsule by unencapsulated strains of Streptococcus pneumoniae. The molecular basis of this phenomenon was not understood, however, before DNA was identified as the transforming agent by Avery and co-workers (Avery et al., 1944). Bacteria that are competent for natural transformation have the ability to take up naked DNA from the environment and incorporate it into their genomes by homologous recombination. It has been known for decades that some streptococcal species spontaneously and transiently differentiate into the competent state when cultivated in certain media in the laboratory. Virtually all of these species, of which S. pneumoniae is by far the best studied, belong to the mitis phylogenetic group (Fig. 1). The exception is Streptococcus mutans, the principal microbial aetiological agent of dental caries, which is the only known naturally transformable member of the mutans group (Perry and Kuramitsu, 1981). In the mid90s, it was discovered that competence in mitis and anginosus groups are regulated by secreted competence stimulating peptides (CSPs) in a quorum sensing-like manner (Håvarstein et al., 1995; 1997). A few years later, a signalling peptide of the CSP type was found to be involved in the regulation of natural transformation in S. mutans as well (Li et al., 2001). Mature CSP is derived from a ribosomally synthesized precursor, ComC, which is processed concomitant with export by the ComAB secretion apparatus (Hui and Morrison, 1991; Håvarstein et al., 542 L. S. Håvarstein 䊏 Fig. 1. Phylogenetic tree based on streptococcal 16S rRNA sequences. The colour indicates the nature of the competence regulatory system found in each phylogenetic group. Red, ComCDE; green, ComRS and yellow, both ComCDE and ComRS. In case of the mutans group, only S. mutans has been investigated. The illustration is adapted from Kawamura et al. (1995) with permission from the publishers. 1995). The extracellular concentration of CSP is monitored by a two-component regulatory system consisting of the transmembrane histidine kinase ComD and its cognate response regulator ComE (Pestova et al., 1996). Sequencing of a number of comC genes from mitis streptococci revealed that a large variety of CSPs are produced by different strains and species belonging to this phylogenetic group. In general, CSP pheromones are highly specific, and are not recognized by non-cognate receptors. As a result, only streptococci belonging to the same pherogroup are able to communicate through CSP signalling. When the external CSP concentration reaches a threshold level phosphorylated ComE directly activates transcription of the early competence genes, including the gene encoding the alternative sigma factor ComX. ComX directs expression of the late competence genes, most of which are involved in DNA uptake and processing (Lee and Morrison, 1999). Orthologs of ComX, designated SigX in the pyogenic streptococci, have been detected in all streptococcal genomes sequenced so far. In fact, they appear to be present in the genomes of all species belonging to the order Lactobacillales (Martin et al., 2006). Genes involved in natural transformation, so called competence genes, are not found in a single locus, but are dispersed throughout the chromosome of bacteria containing them. Interestingly, homologues of competence genes are quite widespread among bacteria, and are present in the genomes of a large number of species that have never been observed to be naturally transformable. The role of these genes in seemingly noncompetent bacteria has been subject to much speculation but little systematic study. It has been proposed that they serve a different function in non-competent bacteria, or represent remnants of once functional competence genes. A third and more interesting possibility is that most apparently non-competent bacteria, possessing the core competence genes essential for DNA uptake and processing, are in reality naturally transformable when the right growth conditions and/or specific environmental cues are present. This was indeed shown to be the case for Vibrio cholerae, which was found to be become competent when subjected to chitin, increasing cell density or stress (Meibom et al., 2005). In the genus Streptococcus recent developments tell a similar story. A species within the salivarius group, the dairy starter bacterium Streptococcus thermophilus LMG 18311, turned out to become naturally transformable when ComX was overexpressed from an inducible promoter (Blomqvist et al., 2006). This finding proved that the ComX regulon, i.e. the core competence genes of S. thermophilus LMG 18311, is functional despite the fact that spontaneous competence development had never been observed in this species. A few years later it was discovered that cultivation of S. thermophilus strain LMD-9 in a synthetic medium resulted in spontaneous competence development during early exponential phase, and that competence development depended on the Ami oligopeptide transport system (Gardan et al., 2009). Considering that the comCDE genes are missing in S. thermophilus, these findings strongly suggested that competence in this species is regulated by an alternative mechanism involving the Ami transporter. In other Gram-positive bacteria, such as Enterococcus faecalis and Bacillus subtilis, oligopeptide transporters are known to be part of signalling pathways regulating conjugation and competence development respectively (Leonard et al., 1996; Pottathil and Lazazzera, 2003). Their role is to import oligopeptide © 2010 Blackwell Publishing Ltd, Molecular Microbiology, 78, 541–544 Competence in the genus Streptococcus 543 signals that bind to and modify the activity of intracellular effector molecules (Shi et al., 2005). Very recently, Fontaine et al. (2010) succeeded in identifying the S. thermophilus competence pheromone as well as its intracellular target protein. The novel oligopeptide pheromone, ComS, turned out to be a short hydrophobic peptide (~7 amino acids), which is cleaved by an unknown mechanism from the C-terminal end of a 24 amino acid ribosomally synthesized precursor. Although not yet formally proven, it is very likely that intracellular ComS interacts with and activates ComR, a transcriptional regulator belonging to the Rgg family. The current working model predicts that activated ComR binds to an inverted repeat motif upstream the comX gene and initiates expression of this gene followed by ComX-mediated competence induction. Remarkably, in this issue of Molecular Microbiology Mashburn-Warren et al. (2010) provide convincing evidence that competence in a number of streptococci belonging to the pyogenic and bovis groups (Fig. 1), which so far have proven refractory to transformation even though they possess the core competence genes (Martin et al., 2006; Woodbury et al., 2006), is regulated by a system closely related to the one operating in S. thermophilus. Consequently, it is very likely that the pyogenic and bovis streptococci are naturally transformable after all, and that they will develop the competent state spontaneously when grown under the appropriate conditions. Curiously, the discoveries described above show that competence development in the genus Streptococcus is regulated by two completely different quorum sensing-like systems. ComCDE controls competence in members of the mitis and probably also in the anginosus group, whereas ComRS perform the same function in the pyogenic, salivarius and bovis groups (Fig. 1). Even more curious is the fact that S. mutans possesses both systems. Almost a decade ago it was observed that unlike S. pneumoniae, inactivation of each of the comCDE genes reduced but did not eliminate competence in S. mutans (Li et al., 2001). This puzzling observation can now be explained by taking into account the new parallel ComRS regulatory system reported in the current edition of this journal (Mashburn-Warren et al., 2010). In contrast, knocking out the ComRS system in S. mutans renders the bacterium completely non-competent. Thus, while the ComRS system is able to function in the absence of ComCDE, the reverse is not true. This indicates that ComR and not ComE is the proximal regulator of ComX in S. mutans (Mashburn-Warren et al., 2010). A possible explanation for the existence of two different mechanisms controlling competence development in streptococci is that ComRS represents an ancestral system that during evolution has been replaced by ComCDE in the mitis and anginosus groups. If this is what happened, where did the ComCDE system come from? Most bacteria in the order Lactobacillales produce bacteriocins, antimicrobial peptides that kill or inhibit the growth of other bacteria. In streptococci production of bacteriocins is frequently regulated by two-component signal transduction pathways of the ComCDE type. Indeed, the ComCDE systems of S. pneumoniae and S. mutans both regulate production of class II bacteriocins in addition to competence development (Guiral et al., 2005; van der Ploeg, 2005). The major pneumococcal system governing bacteriocin production, BlpCHR, operates independently of the closely related ComCDE system. ComCDE-mediated competence development takes place at early logarithmic phase, whereas BlpCHR controlled synthesis of bacteriocins starts when pneumococcal cultures approach the stationary phase (de Saizieu et al., 2000). It is conceivable that a recombination event could have replaced a ComR-type binding site with a ComE/BlpR-type binding site upstream the ComX gene in the common ancestor of bacteria belonging to the mitis and anginosus groups. This would have resulted in an immediate shift from a ComRS to a ComCDE-driven competence regulation system. At present, however, the opposite process cannot be ruled out. Interestingly, the two systems seem to be activated by different environmental condition. Whereas rich complex media stimulate ComCDE expression and competence in mitis group streptococci, these conditions appear to inhibit spontaneous competence development in streptococci carrying the ComRS system. Consequently, the ComRS/ComCDE shift discussed above may represent an example of an evolutionary leap that had profound and lasting consequences for the affected streptococcus and its descendants. Acknowledgements This work was supported by The Research Council of Norway. References Avery, O.T., MacLeod, C.M., and McCarty, M. 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