Cholesterol‐dependent cytolysins: The outstanding questions

Abstract

The cholesterol-dependent cytolysins (CDCs) are a major family of bacterial pore-forming proteins secreted as virulence factors by Gram-positive bacterial species. CDCs are produced as soluble, monomeric proteins that bind specifically to cholesterol-rich membranes, where they oligomerize into ring-shaped pores of more than 30 monomers. Understanding the details of the steps the toxin undergoes in converting from monomer to a membrane-spanning pore is a continuing challenge. In this review we summarize what we know about CDCs and highlight the remaining outstanding questions that require answers to obtain a complete picture of how these toxins kill cells. K E Y W O R D S CD59, cholesterol-binding protein, cholesterol-dependent cytolysin, intermedilysin, MACPF, membrane-protein interactions, perfringolysin O, pneumolysin, pore-forming toxin 1 | INTRODUCTION Pore-forming toxins (PFTs), bacterial toxins that act via membrane permeabilization, are typically produced to aid bacterial virulence or survival. Cholesterol-dependent cytolysins (CDCs) are a large family of PFTs observed in numerous Gram-positive bacterial genera including Streptococcus, Clostridium, Listeria, and Gardnerella.

Differential Effects of Rhodococcus equi Virulence-Associated Proteins on Macrophages and Artificial Lipid Membranes

“…Since VapA is a membrane-active protein, it might well bind more strongly to one membrane curvature over another, but no comparative binding studies have yet been published. Cholesterol, which is required for the binding and function of many bacterial membrane-active proteins ( 38 ), influenced the binding of neither rVapA nor rVapB except that rVapA bound better when PA was also present ( Fig. 5D ).…”

Characterization of tigurilysin, a novel human CD59-specific cholesterol-dependent cytolysin, reveals a role for host specificity in augmenting toxin activity

“…Studies with toxins such as PLY have shown that CDCs often play important roles in bacterial progression from colonization to infection by contributing to inflammation or transmission [42]. Sublytic concentrations of CDCs can lead to a slew of host cell responses that help bacterial proliferation [44,45]. It is therefore conceivable that TGY could play roles in propagating opportunistic infections.…”

Membrane-penetrating peptide from the translocation region ofBordetellaAdenylate Cyclase Toxin prevents toxin cytotoxicity on target cells

“…Binding of toxin monomers to the membrane, and their correct insertion and oligomerization into the lipid bilayer, are essential steps common in the action mechanisms of protein toxins acting at the cell membrane. Membrane lipids such as sphingomyelin and cholesterol have been shown for several protein toxins to have an essential role by favoring one or more of these steps [32][33][34]. In recent years, experimental evidences have shown that several RTX toxins including the leukotoxin (LtxA) from Aggregatibacter actinomytemcomitans, the Escherichia coli hemolysin (HlyA) and RtxA cytolysin from Kingella kingae, require membrane cholesterol for their correct lytic functions [35][36][37].…”