Lipid and phase specificity of α-toxin from S. aureus

Abstract

The pore forming toxin Hla (α-toxin) from Staphylococcus aureus is an important pathogenic factor of the bacterium S. aureus and also a model system for the process of membrane-induced protein oligomerisation and pore formation. It has been shown that binding to lipid membranes at neutral or basic pH requires the presence of a phosphocholine-headgroup. Thus, sphingomyelin and phosphatidylcholine may serve as interaction partners in cellular membranes. Based on earlier studies it has been suggested that rafts of sphingomyelin are particularly efficient in toxin binding. In this study we compared the oligomerisation of Hla on liposomes of various lipid compositions in order to identify the preferred interaction partners and conditions. Hla seems to have an intrinsic preference for sphingomyelin compared to phosphatidylcholine due to a higher probability of oligomerisation of membrane bound monomer. We also can show that increasing the surface density of Hla-binding sites enhances the oligomerisation efficiency. Thus, preferential binding to lipid rafts can be expected in the cellular context. On the other hand, sphingomyelin in the liquid disordered phase is a more favourable binding partner for Hla than sphingomyelin in the liquid ordered phase, which makes the membrane outside of lipid rafts the more preferred region of interaction. Thus, the partitioning of Hla is expected to strongly depend on the exact composition of raft and non-raft domains in the membrane.

Inhibition of Bacterial Toxin Activity by the Nuclear Stain, DRAQ5™

“…We have previously shown that, like other bacterial toxins, e.g., (Alonso et al , 2000; Boesze-Battaglia et al , 2009; Farrand et al , 2010; Lai et al , 2013; Maxfield and Tabas, 2005; Patel et al , 2002; Schwiering et al , 2013; Zitzer et al , 2001), LtxA requires cholesterol in the plasma membrane to bind and kill target cells (Brown et al , 2013; Brown et al , 2015; Fong et al , 2006). Thus, it is possible that the cell counteracts DRAQ5 ™ -mediated decreases in the plasma membrane fluidity by decreasing the membrane cholesterol composition and that this change inhibits LtxA internalization.…”

Staphylococcus aureus α-Toxin: Nearly a Century of Intrigue

“…Lending support to the former mechanism, (1) α-toxin binds to artificial lipid membranes, and can perforate lipid vesicles leading to the release of intravesicular contents [52,66,83,84,85,86,87,88,89]; (2) the “rim-stem crevice” of the toxin directly interacts with membrane lipids [90]; (3) cholesterol depletion abrogates binding of α-toxin to host cell membranes [82]; and (4) the addition of exogenous phosphocholine antagonizes toxin binding [82]. Further, multiple bacterial pore-forming cytotoxins utilize membrane lipids as their cellular receptors establishing a precedent for this mode of interaction [91].…”

Th2 Cytokines Increase Staphylococcus aureus Alpha Toxin–Induced Keratinocyte Death through the Signal Transducer and Activator of Transcription 6 (STAT6)

“…Cell death induced by S. aureus is primarily mediated by secretion of alpha toxin (Bubeck Wardenburg et al , 2007; Taubler et al , 1963), a destructive pore-forming toxin that is often found in the lesions of patients with severe AD (Travers et al , 2001; Wichmann et al , 2009). Alpha toxin induced cell lysis requires that the host express the lipid, sphingomyelin, on its cell surface (Schwiering et al , 2013; Watanabe et al , 1987). It has been reported that alpha toxin specifically recognizes the phosphocholine head group of sphingomyelin (Valeva et al , 2006).…”