Structure, function, and biology of the Enterococcus faecalis cytolysin

Abstract

Enterococcus faecalis is a Gram-positive commensal member of the gut microbiota of a wide range of organisms. With the advent of antibiotic therapy, it has emerged as a multidrug resistant, hospital-acquired pathogen. Highly virulent strains of E. faecalis express a pore-forming exotoxin, called cytolysin, which lyses both bacterial and eukaryotic cells in response to quorum signals. Originally described in the 1930s, the cytolysin is a member of a large class of lanthionine-containing bacteriocins produced by Gram-positive bacteria. While the cytolysin shares some core features with other lantibiotics, it possesses unique characteristics as well. The current understanding of cytolysin biosynthesis, structure/function relationships, and contribution to the biology of E. faecalis are reviewed, and opportunities for using emerging technologies to advance this understanding are discussed.

Figure 1

E. faecalis cytolysin expression. (A) Cytolysin operon in the inactive and active states. In the inactive state, CylR2 binds to the P_Lys (P_L) promoter [68]. Autoinduction via quorum sensing triggers an inferred change in the binding of the cytolysin promoter by the CylR2 protein, resulting in high-level expression of the cytolysin operon [67]. (B) Cytolysin processing and secretion. Large and small subunits are post-translationally modified by CylM [65], secreted and trimmed by CylB [41], and further processed by CylA [64]. (C) Cytolysin activity, in the absence and presence of target cells. In the absence of target cells the subunits form inactive and insoluble multimeric complexes. In the presence of target cells they coordinate to form a pore in the target cell membrane [71].

Figure 2

Sequences and structures of the E. faecalis cytolysin subunits. (A) Primary amino acid sequences of the cytolysin subunits CylL_L and CylL_S. Arrows indicate sites of proteolytic cleavage by CylB and CylA [69], and brackets show the positions of lanthionine and methyllanthionine bridges. (B) Structures of the processed mature cytolysin subunits. Image is reproduced with permission from [76].