VacA polymorphism and function. (a) VacA polymorphism. The gene, vacA, is a polymorphic mosaic with two possible signal regions, s1 and s2, and two possible mid-regions, m1 and m2. The translated protein is an autotransporter with N- and C-terminal processing during bacterial secretion. The s1 signal region is fully active, but the s2 region encodes a protein with a different signal-peptide cleavage site, resulting in a short N-terminal extension to the mature toxin that blocks vacuolating activity and attenuates pore-forming activity. The mid-region encodes a cell-binding site, but the m2 type binds to and vacuolates fewer cell lines in vitro. (b) VacA biological activities. Secreted VacA forms monomers and oligomers; the monomeric form binds to epithelial cells both nonspecifically and through specific receptor binding, for example, to Ptprz, which may modulate cell signaling. Membrane-bound VacA forms pores. Following VacA endocytosis, large vacuoles form, but, although marked in vitro, these are rarely seen in vivo. VacA also induces apoptosis, in part by forming pores in mitochondrial membranes, allowing cytochrome c (Cyt c) egress. Although the presence of cytoplasmic VacA is implied rather than demonstrated, yeast two-hybrid experiments show potential for specific binding to cytosolic targets including cytoskeletal proteins, consistent with observed cytoskeletal effects. Finally, VacA has suppressive effects on immune cell function. The relative importance of these effects on H. pylori persistence and host interaction remains unclear.