Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13473-8. doi: 10.1073/pnas.1001815107. Epub 2010 Jul 12.
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.
金黄色葡萄球菌α-溶血素（Hla）是一种有效的细胞毒素，在金黄色葡萄球菌病的发病机制中起重要作用，包括耐甲氧西林的流行株引起的疾病。Hla 作为一种水溶性单体分泌，经历一系列构象变化，在宿主膜中生成七聚体、β-桶状结构。Hla 的结构成熟取决于其在细胞膜背景下与一种先前未知的蛋白受体相互作用。本文报道了一种解整合素和金属蛋白酶 10（ADAM10）与 Hla 相互作用，并启动一系列事件，使毒素转化为细胞毒性孔。Hla 与真核细胞的结合需要 ADAM10 的表达。此外，ADAM10 是 Hla 介导的细胞毒性所必需的，尤其是当毒素浓度较低时。这些数据表明 ADAM10 可能是高亲和力的毒素受体。Hla 结合后，ADAM10 重新定位于富含 caveolin 1 的脂筏，作为信号分子聚集的平台。本文证明，Hla-ADAM10 复合物引发细胞内信号事件，最终导致粘着斑的破坏。
