The outer surface protease, SepM, is required for blp locus activation in three of the four most common pherotypes of Streptococcus pneumoniae

Streptococcus pneumoniae (pneumococcus) is an important human pathogen that primarily resides in the nasopharynx. To persist in this polymicrobial environment, pneumococcus must compete with other members of the bacterial community. Competition is mediated in part by the action of the blp locus which encodes a variable array of bacteriocins and their associated immunity proteins. The locus is controlled by a two-component regulatory system that senses the extracellular concentration of the peptide pheromone, BlpC. There are four major pherotypes of BlpC that can be found in most pneumococcal genomes. Here, we show that the protease, SepM, is required for activation of three of the four major pherotypes. The only SepM independent BlpC type is 9AA shorter than the SepM-dependent peptides, consistent with a cleavage event at the C-terminal end. The processing event occurs following secretion and removal of the C terminal region is required for binding to the histidine kinase receptor. Synthetic truncated peptides or full-length peptides pre-incubated with SepM-expressing bacteria can upregulate the blp locus independent of SepM. We show that SepM-independent peptides accumulate in the supernatant of secreting cells at low levels suggesting a role for the tail in peptide secretion, stability or solubility and demonstrating a significant tradeoff for SepM-independence.