The concerted action of the Helicobacter pylori cytotoxin VacA and of the v-ATPase proton pump induces swelling of isolated endosomes

Abstract

SummaryThe vacuolating cytotoxin (VacA) is a major virulence factor of Helicobacter pylori, the bacterium associated to gastroduodenal ulcers and stomach cancers. VacA induces formation of cellular vacuoles that originate from late endosomal compartments. VacA forms an anion-selective channel and its activity has been suggested to increase the osmotic pressure in the lumen of these acidic compartments, driving their swelling to vacuoles. Here, we have tested this proposal on isolated endosomes that allow one to manipulate at will the medium. We have found that VacA enhances the v-ATPase proton pump activity and the acidification of isolated endosomes in a Cl

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus

“…We also observed intracellular vacuolization, which has also been attributed to Rab7 hyperactivation (Genisset et al, 2007;Haas et al, 1995;Papini et al, 1997;Schimmoller and Riezman, 1993). We were unable to rescue the defects in EGFR degradation and lysosomal function by Rab7 silencing or by expressing its dominant-negative mutant (data not shown), possibly due to the requirement of a delicate level of Rab7 activation for these processes.…”

“…Moreover, intracellular vacuolization due to late endosome swelling has been observed upon inhibition of Vps34 (Jaber et al, 2012;Johnson et al, 2006;Reaves et al, 1996;Ronan et al, 2014). Rab7 activation has been reported to be essential for vacuolization in several conditions, such as in yeast and during Helicobacter pylori infection (Genisset et al, 2007;Haas et al, 1995;Papini et al, 1997;Schimmoller and Riezman, 1993). Given that we observed Rab7 hyperactivation in Vps34…”

Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

“…Microinjection of VacA or the transfection of plasmids containing the vacA gene into HeLa cells resulted in the formation of intracellular vacuoles , providing evidence that VacA introduced into the cytosol acts on an intracellular target; potential targets include the vacuolar ATPase (V-ATPase), Rab7, and Rac1 Hotchin et al 2000). It has been well established that VacA-induced vacuolation requires V-ATPase activity, and that its inhibitor, bafilomycin A1, reduced VacA-induced vacuolation in mammalian cells (Suzuki et al 2001;Genisset et al 2007). Rab7 may be important for supporting membrane deposition and homotypic fusion between late endosomes.…”

Gastric Helicobacters in Domestic Animals and Nonhuman Primates and Their Significance for Human Health

“…The vacuolating toxin VacA plays a role in the development of vacuoles in epithelial cells and in the induction of apoptosis of these cells (32,132). It is involved in the osmotic swelling of endosomes into vacuoles (79) and is encoded by the vacA gene, which possesses several polymorphic sites, namely, the signal region, the midregion and the intermediate region. For the first two regions, H. pylori strains with vacA type s1/m1 have been shown to be associated with duodenal and gastric ulceration and gastric adenocarcinoma, whereas the intermediate region is an important marker for H. pylori strains associated with gastric adenocarcinoma (188).…”