Helicobacter pylori vacuolating toxin accumulates within the endosomal‐vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia

High Cell Sensitivity toHelicobacter pyloriVacA Toxin Depends on a GPI-anchored Protein and is not Blocked by Inhibition of the Clathrin-mediated Pathway of Endocytosis

“…After internalization, VacA localizes in the endocytic-endosomal compartment from which vacuoles originate (Ricci et al, 1993(Ricci et al, , 1997. Vacuole development is strictly dependent on the presence in the incubation medium of weak bases like ammonia (which can be generated by H. pylori urease) Ricci et al, 1997). The finding of VacA in both endosomal tubulovesicles and vacuoles (Ricci et al, 1997;Sommi et al, 1998) further supports the hypothesis that the origin of vacuoles is endosomal.…”

“…VacA has been reported to bind to specific, high-affinity cell surface receptors (Yahiro et al, 1997(Yahiro et al, , 1999Massari et al, 1998;Seto et al, 1998) and to be internalized by cells via a temperature-dependent process (Garner and Cover, 1996). After internalization, VacA localizes in the endocytic-endosomal compartment from which vacuoles originate (Ricci et al, 1993(Ricci et al, , 1997. Vacuole development is strictly dependent on the presence in the incubation medium of weak bases like ammonia (which can be generated by H. pylori urease) Ricci et al, 1997).…”

Helicobacter pylori vacuolating toxin

“…However, it is now widely accepted that VacAinduced vacuoles derive from the endocytic-endosomal compartment, where the toxin localizes after internalization, and that such structures are distinct and different from autophagosomes [14,110,168,[180][181][182]. Montecucco and coworkers [180,[183][184][185] demonstrated that vacuoles originate from an acidic late endosomal compartment and that VacA induces the formation of a hybrid compartment with markers of both LEs and lysosomes (such as Rab7 and Lgp110, respectively), but with a reduced proteolytic activity.…”

“…VacA by itself is apparently not vacuolating, but it greatly increases the vacuolating activity of weak bases [109,181]. Weak bases are indeed well known to cause vacuolation in eukaryotic cells: they cross cell membranes in an uncharged state and are trapped by protonation within acidic compartments of the cell, thereby inducing osmotic swelling of these compartments, resulting in vacuole development [186,187].…”

“…The lumen of VacA-induced vacuoles has been reported to apparently lack both intravesicular membrane structures, characterizing the late endosomal compartment from which vacuoles originate, and lyso-bisphosphatidic acid, a key component of such internal membrane structures [178,179,181,194]. Based on these findings, Montecucco and coworkers [194,196] suggested that the source of membrane required for progressive vacuole enlargement might be represented by such late endosomal internal membranes, which would undergo fusion with the limiting membrane of LEs/nascent vacuoles.…”