Staphylococcus aureus recruits Cdc42GAP through recycling endosomes and the exocyst to invade human endothelial cells

Activation and invasion of the vascular endothelium by Staphylococcus aureus (S. aureus) is a major cause of sepsis and endocarditis. For endothelial cell invasion, S. aureus triggers actin polymerization via Cdc42, N-WASp and Arp2/3 complex to assemble a phagocytic cup-like structure. Here we show that after stimulating actin polymerization staphylococci recruit Cdc42GAP which deactivates Cdc42 and terminates actin polymerization in the phagocytic cups. Cdc42GAP is delivered to the invading bacteria on recycling endocytic vesicles in concert with exocyst complex. When Cdc42GAP recruitment by staphylococci was prevented by blocking recycling endocytic vesicles or exocyst complex or when Cdc42 was constitutively activated, phagocytic cup closure was impaired and endothelial cell invasion was inhibited. Thus, to complete invasion of the endothelium staphylococci reorient recycling endocytic vesicles to recruit Cdc42GAP which terminates Cdc42-induced actin polymerization in phagocytic cups. Analogical mechanisms may govern other Cdc42-dependent cell functions.