Cholesterol-Dependent Cytolysins, a Family of Versatile Pore-Forming Toxins

Abstract

The cholesterol-dependent cytolysins (CDCs) are a large family of pore-forming toxins that are produced by more than 20 species from the genera Clostridium, Streptococcus, Listeria, Bacillus, and Arcanobacterium. The pore-forming mechanism of these toxins exhibits two hallmark characteristics: an absolute dependence on the presence of membrane cholesterol and the formation of an extraordinarily large pore. Each CDC is produced as a soluble monomeric protein that, with the exception of one member, is secreted by a type II secretion system. Upon encountering a eukaryotic cell, the CDCs undergo a transformation from a soluble monomeric protein to a membrane-embedded supramolecular pore complex. The conversion of the monomers to an oligomeric, membrane-inserted pore complex requires some extraordinary changes in the structure of the monomer, yet the mechanism of pore formation may be only the beginning of the CDC story.Although the CDCs are well known as beta-hemolytic proteins, it has become increasingly apparent that bacterial pathogens use these proteins in much more sophisticated ways than as simple hemolysins or general cell-lytic agents. The CDC structure also exhibits a plasticity that has allowed the evolution of unique features for some CDCs, without compromising the fundamental pore-forming mechanism. Some of these features are reflected in CDCs that activate complement, that utilize a nonsterol receptor, that exhibit a pH-sensitive, poreforming mechanism, or that can function as a protein translocation channel. As will be apparent in this review, our knowledge of how the CDCs are used by pathogens lags behind our understanding of the CDC pore-forming mechanism, although some studies have provided some provocative glimpses into how the bacterial cells use CDCs during an infection. This review will focus on the advancements in our understanding of the CDC pore-forming mechanism, the unique structural and mechanistic features that are exhibited by many of the CDCs, and how these features might contribute to pathogenesis.

Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

“…Domain 4 also participates in the binding of hCD59 to C8a and C9. 30,33 We have consistently demonstrated that rILYd4 specifically abrogates hCD59 function in both normal human cells and B lymphoma cells. Furthermore, we demonstrated that rILYd4 (IC 50 533 nM) restores the sensitivity of a rituximabresistant NHL cell line to the rituximab CDC effect.…”

Sterol and pH Interdependence in the Binding, Oligomerization, and Pore Formation of Listeriolysin O

“…LLO belongs to a family of cholesterol-dependent cytolysins (CDC) secreted by Gram-positive bacteria (7,8). More than 20 members have been described, including perfringolysin from Clostridium perfringens, streptolysin O from Streptococcus pyogenes, pneumolysin from Streptococcus pneumoniae, etc.…”

“…After the binding, monomers diffuse in the plane of the membrane to form a prepore complex (17), and finally, each monomer contributes two -hairpins, formed from two pairs of R-helices from domain 3, to form a final oligomeric -barrel pore (18,19). Pores formed by CDC are large structures with a diameter of 25-35 nm and are composed of 35-50 monomers (7,8). LLO has an acidic pH optimum of activity (5,(20)(21)(22), and this unique property in the CDC family (7) ensures maximal activity in phagocytic vacuoles and low activity in the cytoplasm of the host cells.…”

Crystal structure of listeriolysin O reveals molecular details of oligomerization and pore formation

“…LLO takes a special position among the CDCs as it enables L. monocytogenes to live inside host cells, a feature that is not shared by other CDC-producing bacteria 23 . In addition, LLO is a promising target for the development of antitumor vaccines 24 .…”