# Quorum Sensing Regulation of Competence and Bacteriocins in _Streptococcus pneumoniae_ and _mutans_
## 7 The Multiple Layers of Competence Regulation in _Streptococcus mutans_
The ComS pre-peptide is exported and processed via an unknown mechanism (denoted as a dotted line and gray box) into XIP. In a chemically defined, peptide-poor medium (CDM) XIP is re-imported via oligopeptide permease (Opp) and binds ComR. The ComR/XIP complex binds upstream of _comS_ and _sigX_ at P\({}_{ComR}\)-box sites [31]. The alternative sigma factor, SigX, facilitates RNA polymerase (RNAP) binding at P\({}_{cin-box}\) sites [64]. Genes regulated by SigX include the DNA-uptake and transformasome machinery as well as the murein hydrolase, Lytts_m_, among others [59; 68]. Non-specific peptides present in high concentrations in peptide-rich media are thought to prevent intracellular transport of XIP via Opp [69]. Recently, a link between the bacteriocin and competence pathways was determined to be mediated by SigX at a _P\({}_{cin-box}\)_ site upstream of _blpRH_ (formerly referred to as _comDE_, see Table 1). The BlpRH QS pathway pheromone, MIP, is exported and processed by the ABC transporter complex NlmTE into the 21 amino-acid long precursor peptide, MIP-21 [27]. Cleavage of MIP-21 by the protease SepM results in fully active MIP-18 [11]. MIP-18 is thought to bind to BlpH, resulting in activation and phosphorylation of BlpR similarly to CSP binding and activation of ComDE in _S. pneumoniae_[13]. BlpR-P binds at P\({}_{BlpR-box}\) sites upstream of bacteriocin loci such as _cipB_ and _nlmAB_, among others [70]. Although the mechanism is unknown (represented by the dotted circle surrounding CiPB), the activity of CiPB is required for the indirect induction of SigX observed when cells are grown in peptide-rich media and treated with MIP [22; 25; 71]. Multiple other regulatory pathways are observed to feed into the ComRS/BlpRH QS networks, such as the CiaHR, HdrRM, and the RcrRPQ systems [72; 73; 74; 75; 76; 77]. These additional inputs along with possible contribution through the BlpRH-regulated QS pathway (i.e., via _cipB_ expression [71]) may help _S. mutans_ to integrate environmental cues into the competence signaling cascade, allowing for fine tune control of natural transformation (depicted by the blue block arrow). How Does Peptide-Rich Versus Peptide-Poor Medium Affect Competence and Bacterioin QS Pathways? : \"The Medium Is the Message\"--_[PERSON]_[78]  
Just as the relationship between the regulation of competence and bacteriocin production in _S. pneumoniae_ has proven to involve complex and tightly regulated pathways, so too does this relationship appear within _S. mutans_. The discovery of the ComRS pathway not only revealed the proximal regulator of SigX in _S. mutans_, but also emphasized the critical importance of growth medium on the phenomenon of competence induction [31]. Recent studies have described two distinct patterns in SigX activation in response to the two known competence-inducing pheromones, XIP and MIP. Spontaneous activation of SigX during the onset of stationary phase occurs as a result of endogenous production of XIP when cells are grown in a chemically defined medium (CDM) that is rich in amino acids but devoid of nutrient peptides [62]. Likewise, SigX in _S. mutans_ growing in exponential phase can be stimulated with low amounts (0.01 uM) of exogenously provided XIP. However, an XIP response does not occur in peptide-rich media (where peptides are added as nutrient supplements from sources like pepitone), unless high concentrations (>1 uM) of XIP are provided exogenously [79]. It is thought that XIP must compete with non-specific peptides for entry to the cell through the Opp/Ami peptide transporter, and therefore peptide-rich media inhibit this process [69; 79]. Conversely, mutacin-inducing peptide (MIP, previously referred to as CSP; see Table 1) causes SigX induction when cells are grown in peptide-rich media, but does not result in observable expression of SigX in CDM. The failure of MIP to induce SigX in CDM cannot be attributed to inactive pheromone, as MIP treatment does activate expression of the bacteriocin CipB (Mutacin V/NlmC), via the activity of BlpR (the _S.