# Quorum Sensing Regulation of Competence and Bacteriocins in _Streptococcus pneumoniae_ and _mutans_
## 5 A Second Bacteriocin QS System Cryptically Linked to Competence in _S. pneumoniae_  
Recently, new evidence has demonstrated that a separate bacteriocin QS pathway may contribute to the acquisition of DNA by competent pneumococcal cells [33; 34]. As previously mentioned, when [PERSON] et al. [20] originally described the temporally distinct gene sets activated post-CSP induction, a bacteriocin-like peptide (blp) ABC transporter, _blpAB_, was found to be among the early genes. Curiously, there is no clear Ceb-containing promoter site located upstream of this locus. Additionally, oriented in the opposite direction but directly adjacent to this locus is a pair of putative bacteriocin immunity genes, _blpY_ and _blpZ_, that were also observed to be early genes, also without an obvious upstream Ceb element [20].  
Although these loci had not yet been studied in relation to competence in _S. pneumoniae_ at the time, they had been observed to be regulated by the BlpRH TCST QS pathway, which is implicated in virulence in a mouse infection model [51]. Upon detailed inspection, [PERSON] et al. [38] noted the high degree of similarity between the streptococcal _blpAB_ and _comAB_ sequences (65% and 31% identity is shared between the A and B subunits, respectively) [52]. Significantly, directly downstream of _blpAB_, there is a small open reading frame (ORF), now termed _blpC_, encoding a double-glycine motif and possessing leader peptide homology to the family of class II bacteriocin peptides, which also includes CSP [8; 38]. Intriguingly, only \(\sim\)20%-30% of all sequenced _S. pneumoniae_ isolates encode a (predicted) functional _blpAB_ locus [34; 52].  
Further characterization of the Blp pathway revealed additional similarities to the ComABCDP pathway that regulates competence. For example, mature BlpC peptide pheromone was found to activate the histidine kinase receptor, BlpH, which in turn resulted in phosphorylation of the response regulator BlpR, paralleling the signaling mechanism of CSP [38]. Among the genes up-regulated upon BlpC induction are _blpABC_, _blpXYZ_, and _blpSRH_, as well as several putative bacteriocins and related immunity proteins that constitute the Bacteri Immunity Region (BIR) [38; 53; 54]. Analysis of the major BlpC-induced transcripts resulted in the identification of a highly conserved consensus promoter element predicted to bind activated BlpR. Upon inspection of the _S. pneumoniae_ genome, no additional putative BlpR promoter sites were identified, even in regions upstream of the genes known to directly regulate competence [38]. This observation, along with the finding that _blpA_ is not essential for transformation under laboratory conditions, hindered the connection between this bacteriocin pathway and the CSP-regulated competence [20; 38].  
In 2004, [PERSON] et al. [40] described the promoter region of an early nonessential competence locus encoding a putative ATP transporter, _qsrAB_, that is induced upon treatment with CSP or with BlpC. Induction relied on the transcriptional regulators ComE and BlpR, suggesting that either factor could induce _qsrAB_[54]. By comparing the upstream regulatory region of _qsrAB_ with the conserved ComE-regulated promoter, [PERSON] and colleagues characterized the _qsrAB_ promoter as having a \"hybrid direct repeat motif\" where the distal motif shares more homology to the conserved _blpR_-regulated promoters and the proximal motif is more similar to the Ceb motif [40] (see Figure 1, inset). By mutating the _comE_-like motif to be more similar to the _blpR_ one, they observed an increased induction of _qsrAB_ by BlpC treatment [40]. This observation that a hybrid direct-repeat promoter could accommodate separate transcriptional regulators, each with its own distinctive target motif, facilitated the discovery that bacteriocin and competence pathways are more closely linked than previously thought.