Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin–mediated cellular injury

GA Wilke, JB Wardenburg - Proceedings of the National …, 2010 - National Acad Sciences
GA Wilke, JB Wardenburg
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
Staphylococcus aureus α-hemolysin (Hla), a potent cytotoxin, plays an important role in the
pathogenesis of staphylococcal diseases, including those caused by methicillin-resistant
epidemic strains. Hla is secreted as a water-soluble monomer that undergoes a series of
conformational changes to generate a heptameric, β-barrel structure in host membranes.
Structural maturation of Hla depends on its interaction with a previously unknown
proteinaceous receptor in the context of the cell membrane. It is reported here that a …
Staphylococcus aureus α-hemolysin (Hla), a potent cytotoxin, plays an important role in the pathogenesis of staphylococcal diseases, including those caused by methicillin-resistant epidemic strains. Hla is secreted as a water-soluble monomer that undergoes a series of conformational changes to generate a heptameric, β-barrel structure in host membranes. Structural maturation of Hla depends on its interaction with a previously unknown proteinaceous receptor in the context of the cell membrane. It is reported here that a disintegrin and metalloprotease 10 (ADAM10) interacts with Hla and is required to initiate the sequence of events whereby the toxin is transformed into a cytolytic pore. Hla binding to the eukaryotic cell requires ADAM10 expression. Further, ADAM10 is required for Hla-mediated cytotoxicity, most notably when the toxin is present at low concentrations. These data thus implicate ADAM10 as the probable high-affinity toxin receptor. Upon Hla binding, ADAM10 relocalizes to caveolin 1-enriched lipid rafts that serve as a platform for the clustering of signaling molecules. It is demonstrated that the Hla–ADAM10 complex initiates intracellular signaling events that culminate in the disruption of focal adhesions.
National Acad Sciences