Abstract
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 9 amino acids 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 preincubated with SepM-expressing bacteria can upregulate the blp locus independent of SepM. We show that naturally secreted 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 trade-off for SepM-independence. IMPORTANCE Streptococcus pneumoniae is an important cause of disease in humans that occurs when the bacteria in the nasopharynx bypasses host defenses to invade deeper tissues. Colonization fitness thus represents an important initial step in pathogenesis. S. pneumoniae produces antimicrobial peptides called bacteriocins that provide a competitive advantage over neighboring bacteria in the nasopharynx. The blp locus encodes a variable array of bacteriocins that participate in competition. Here, we demonstrate that activation of the blp locus requires a surface protease that activates the blp signal peptide. There are naturally occurring signal peptides that do not require cleavage, but these are characterized by poor secretion. We describe an additional, previously unappreciated activation step in the control of bacteriocin production in S. pneumoniae.