Enterococcal Sex Pheromones: Evolutionary Pathways to Complex, Two-Signal Systems

Abstract

bGram-positive bacteria carry out intercellular communication using secreted peptides. Important examples of this type of communication are the enterococcal sex pheromone systems, in which the transfer of conjugative plasmids is controlled by intercellular signaling among populations of donors and recipients. This review focuses on the pheromone response system of the conjugative plasmid pCF10. The peptide pheromones regulating pCF10 transfer act by modulating the ability of the PrgX transcription factor to repress the transcription of an operon encoding conjugation functions. Many Gram-positive bacteria regulate important processes, including the production of virulence factors, biofilm formation, sporulation, and genetic exchange using peptide-mediated signaling systems. The key master regulators of these systems comprise the RRNPP (RggRap/NprR/ PlcR/PrgX) family of intracellular peptide receptors; these regulators show conserved structures. While many RRNPP systems include a core module of two linked genes encoding the regulatory protein and its cognate signaling peptide, the enterococcal sex pheromone plasmids have evolved to a complex system that also recognizes a second host-encoded signaling peptide. Additional regulatory genes not found in most RRNPP systems also modulate signal production and signal import in the enterococcal pheromone plasmids. This review summarizes several structural studies that cumulatively demonstrate that the ability of three pCF10 regulatory proteins to recognize the same 7-amino-acid pheromone peptide arose by convergent evolution of unrelated proteins from different families. We also focus on the selective pressures and structure/function constraints that have driven the evolution of pCF10 from a simple, single-peptide system resembling current RRNPPs in other bacteria to the current complex inducible plasmid transfer system. BACKGROUND AND SIGNIFICANCE

PrgU: a suppressor of sex pheromone toxicity in Enterococcus faecalis

“…Assembly of T4SSs is an energetically expensive process, and tight control of the sex pheromone response might have arisen to mitigate the large fitness costs associated with high-frequency plasmid transfer (Dunny & Berntsson, 2016). Here, we discovered another reason for controlling the sex pheromone response in E. faecalis .…”

“…Many E. faecalis clinical isolates harbor members of a large family of conjugative plasmids whose transmission is induced by sensing of peptide pheromones (Dunny, 2013, Dunny & Berntsson, 2016). These plasmids typically code for antibiotic resistance as well as surface proteins such as bacteriocins (cytolysin) or adhesins (PrgB, Esp) of established importance for tissue attachment and biofilm formation (Clewell et al , 2014).…”

“…One of the best-characterized representatives of the family of pheromone responsive plasmids is the tetracycline-resistance plasmid pCF10 (Dunny, 2013, Dunny & Berntsson, 2016). Detailed studies have unveiled a complex regulatory circuitry that operates to regulate pheromone-dependent expression of the plasmid-borne prgQ operon.…”

Regulation of conjugative transfer of plasmids and integrative conjugative elements

“…The balance between cCF10 and iCF10 will determine whether the operon is induced or not. Additional control of the system is conferred by post-transcriptional modulation (Cook and Federle, 2014; A C C E P T E D M A N U S C R I P T 15 Dunny, 2007;Dunny and Berntsson, 2016).…”

“…Transfer of pSym of R. leguminosarum bv viciae, is induced by a chromosomally encoded homoserine lactone synthase, produced in the plasmid-lacking recipient, that is able to A C C E P T E D M A N U S C R I P T 23 diffuse into the donor and activate the transfer system (Danino et al, 2003). In Grampositive bacteria transfer is often induced by plasmid-less recipients, using chromosomeencoded factors (Dunny and Berntsson, 2016;Goessweiner-Mohr et al, 2014). Transfer of E. coli plasmid F is influenced by the extracellular response element CpxA (Gubbins et al, 2002).…”