title: PepO, a CovRS-controlled endopeptidase, disrupts Streptococcus pyogenes quorum sensing.
abstract: Group A Streptococcus (GAS, Streptococcus pyogenes) is a human-restricted pathogen with a capacity to both colonize asymptomatically and cause illnesses ranging from pharyngitis to necrotizing fasciitis. An understanding of how and when GAS switches between genetic programs governing these different lifestyles has remained an enduring mystery and likely requires carefully tuned environmental sensors to activate and silence genetic schemes when appropriate. Herein, we describe the relationship between the Control of Virulence (CovRS, CsrRS) two-component system and the Rgg2/3 quorum-sensing pathway. We demonstrate that responses of CovRS to the stress signals Mg(2+) and a fragment of the antimicrobial peptide LL-37 result in modulated activity of pheromone signaling of the Rgg2/3 pathway through a means of proteolysis of SHP peptide pheromones. This degradation is mediated by the cytoplasmic endopeptidase PepO, which is the first identified enzymatic silencer of an RRNPP-type quorum-sensing pathway. These results suggest that under conditions in which the virulence potential of GAS is elevated (i.e. enhanced virulence gene expression), cellular responses mediated by the Rgg2/3 pathway are abrogated and allow individuals to escape from group behavior. These results also indicate that Rgg2/3 signaling is instead functional during non-virulent GAS lifestyles.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60607, USA.
authors.forename: Reid V
authors.initials: RV
authors.lastname: Wilkening
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Federle
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D053263:Gene Regulatory Networks; D000071677:Histidine Kinase; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D010675:Pheromones / Q000378:metabolism*; D053038:Quorum Sensing; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D014774:Virulence; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; C432143:CsrR protein, Streptococcus pyogenes; D047908:Intracellular Signaling Peptides and Proteins; D010675:Pheromones; D012097:Repressor Proteins; C534547:CovS protein, Streptococcus pyogenes; D000071677:Histidine Kinase; D010450:Endopeptidases; D008274:Magnesium; D054804:Cathelicidins