Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin–mediated cellular injury
- 12 July 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (30), 13473-13478
- https://doi.org/10.1073/pnas.1001815107
Abstract
Staphylococcus aureus alpha-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, beta-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.Keywords
This publication has 32 references indexed in Scilit:
- Targeting of Alpha‐Hemolysin by Active or Passive Immunization Decreases Severity of USA300 Skin Infection in a Mouse ModelThe Journal of Infectious Diseases, 2010
- Clostridium difficile toxin A binds colonocyte Src causing dephosphorylation of focal adhesion kinase and paxillinExperimental Cell Research, 2009
- Anti-Alpha-Hemolysin Monoclonal Antibodies Mediate Protection againstStaphylococcus aureusPneumoniaInfection and Immunity, 2009
- Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replicationProceedings of the National Academy of Sciences of the United States of America, 2009
- Signal co-operation between integrins and other receptor systemsBiochemical Journal, 2009
- Cytolysins Augment Superantigen Penetration of Stratified MucosaThe Journal of Immunology, 2009
- Vaccine protection againstStaphylococcus aureuspneumoniaThe Journal of Experimental Medicine, 2008
- Crystal structures of VAP1 reveal ADAMs' MDC domain architecture and its unique C-shaped scaffoldThe EMBO Journal, 2006
- Functional form of Caveolin-1 is necessary for the assembly of α-hemolysinBiochemical and Biophysical Research Communications, 2004
- Studies on the binding of staphylococcal 125I-labeled α-toxin to rabbit erythrocytesBiochemistry, 1976