Figure 1

Traffic of VacA. Uptake of VacA into host cells is initiated by binding to lipid rafts. This step can be facilitated by receptor proteins (such as the receptor-like protein tyrosine phosphatases RPTPα and RPTPβ, or - on the surface of leukocytes - by the integrin β₂ subunit CD18). Inside the lipid rafts, VacA binds to sphingomyelin. Subsequent endocytosis is dependent on Cdc42, a small GTPase of the Rho subfamily. The endocytosis is independent of clathrin. VacA accumulates in an early endosomal compartment enriched in GPI-anchored proteins (GEEC). The endosomes recruit cytosolic actin which forms comet-like structures. Growth of the actin fibers causes a significant motility of the endosomes in the cell. Fractions of the endosomes bind the small GTPase Rab5 and are therefore classified as early endosomes. The early endosomes undergo maturation to late endosomes, releasing Rab5 and binding Rab7. VacA in cooperation with V-type ATPases causes swelling of the endosomes and thereby a formation of vacuoles. In parallel, a fraction of the early endosomes attaches to the surface of mitochondria and VacA is transferred. VacA eventually accumulates in the mitochondrial inner membrane, forming chloride channels. Dissipation of the mitochondrial membrane potential causes recruitment of Bax and Bak, release of cytochrome c, and apoptosis. Abbreviations: Bak, Bcl-2-homologous antagonist/killer; Bax, Bcl-2-associated × protein; CD, "cluster of differentiation" (defined molecules of the cell surface); Cdc, "cell division cycle" (indicating a protein involved in the control of the cell cycle); GPI, glycosylphosphatidylinositol (a glycolipid, often attached to the C-terminus of a protein to mediate association with membranes); Rab, "Ras-related in brain" (the Rab family is part of the Ras superfamily of small GTPases); Ras, "rat sarcoma"; Rho, "ras homologous"; TOM, translocase of the mitochondrial outer membrane (a protein complex in the mitochondrial outer membrane mediating protein translocation); VacA, vacuolating cytotoxin A.