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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 abso- lute 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 excep- tion 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 mem- brane-embedded supramolecular pore complex. The conver- sion 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 forma- tion may be only the beginning of the CDC story. Although the CDCs are well known as beta-hemolytic pro- teins, it has become increasingly apparent that bacterial patho- gens 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 evolu- tion of unique features for some CDCs, without compromising the fundamental pore-forming mechanism. Some of these fea- tures are reflected in CDCs that activate complement, that utilize a nonsterol receptor, that exhibit a pH-sensitive, pore- forming mechanism, or that can function as a protein translo- cation channel. As will be apparent in this review, our knowl- edge 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 under- standing 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. OVERVIEW OF THE CDC PORE-FORMING MECHANISM The structures of the soluble monomers of perfringolysin O (PFO) (80) and intermedilysin (ILY) (72) are shown in Fig. 1, and the general features of the CDC pore-forming mechanism are shown in Fig. 2. Both CDCs are -sheet-rich, four-domain proteins. The highly conserved tryptophan-rich undecapeptide is present in domain 4. The undecapeptide appears to mediate the binding of some CDCs to cholesterol-rich membranes, and it has been thought that the undecapeptide may interact di- rectly with cholesterol. However, it has also been shown that at least one CDC from Streptococcus intermedius, ILY, specifi- cally uses human CD59 as its receptor. The undecapeptide has also been shown to insert into the membrane (28, 58), though not to a significant depth (28). In addition, three other short hydrophobic loops juxtaposed to the undecapeptide at the tip of domain 4 have been shown to also insert into the membrane surface and anchor the CDC to the membrane in a perpendic- ular orientation (12, 75, 76).

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