Helicobacter pylori vacuolating toxin A and apoptosis

Abstract

VacA, the vacuolating cytotoxin A of Helicobacter pylori, induces apoptosis in epithelial cells of the gastic mucosa and in leukocytes. VacA is released by the bacteria as a protein of 88 kDa. At the outer surface of host cells, it binds to the sphingomyelin of lipid rafts. At least partially, binding to the cells is facilitated by different receptor proteins. VacA is internalized by a clathrin-independent mechanism and initially accumulates in GPI-anchored proteins-enriched early endosomal compartments. Together with early endosomes, VacA is distributed inside the cells. Most of the VacA is eventually contained in the membranes of vacuoles. VacA assembles in hexameric oligomers forming an anion channel of low conductivity with a preference for chloride ions. In parallel, a significant fraction of VacA can be transferred from endosomes to mitochondria in a process involving direct endosome-mitochondria juxtaposition. Inside the mitochondria, VacA accumulates in the mitochondrial inner membrane, probably forming similar chloride channels as observed in the vacuoles. Import into mitochondria is mediated by the hydrophobic N-terminus of VacA. Apoptosis is triggered by loss of the mitochondrial membrane potential, recruitment of Bax and Bak, and release of cytochrome c.

Role of Connexin 43 in Helicobacter pylori VacA-Induced Cell Death

“…One of the important virulence factors produced by H. pylori is the vacuolating toxin VacA (7)(8)(9)(10)(11)(12)(13)(14). Several host cell factors are known to be required for VacA-induced cellular alterations.…”

“…Gastric cancer is one of the most common infection-related cancers and is the second leading cause of cancer-related death worldwide (5,6). One of the important virulence factors produced by H. pylori is a secreted pore-forming toxin known as VacA (7)(8)(9)(10)(11)(12)(13)(14).…”

“…Multiple types of cells are susceptible to VacA, including gastric epithelial cells and cells of the immune system (1,2,(7)(8)(9)(10)(11)(12)(13)(14)20). As a first step in VacA intoxication, the toxin binds to host cell receptors (7,9).…”

“…There are many possible consequences of VacA interactions with epithelial cells, including cell vacuolation, disruption of endosomal and lysosomal function, depolarization of the plasma membrane potential, permeabilization of epithelial monolayers, detachment of epithelial cells from the basement membrane, autophagy, and cell death (7-14, 20, 32-34). VacA can cause death of gastric epithelial cells through both apoptosis and programmed cell necrosis (14,20,(35)(36)(37).…”

Morphological changes in human gastric epithelial cells induced by nuclear targeting of Helicobacter pylori urease subunit A

“…Several virulence-associated determinants have been found to be associated with the pathogenesis of H. pylori and progression of gastric diseases. These include membrane-associated adhesins (blood-group-antigen-binding adhesin [BabA], sialic acid binding adhesin [SabA], adherence-associated lipoprotein A and B [AlpA/B], and outer inflammatory protein A [OipA]) (Ilver et al, 1998;Yamaoka et al, 2000;Mahdavi et al, 2002;Odenbreit et al, 2002), cytotoxin-associated gene A (CagA) (Handa et al, 2007;Backert et al, 2011;Wessler et al, 2011), vacuolating cytotoxin A (VacA) (Cover and Blanke, 2005;Rassow, 2011), high temperature requirement A (HtrA) (Hoy et al, 2010), peptidoglycan (Viala et al, 2004), and γ-glutamyl transpeptidase (Kim et al, 2007). Nuclear targeting of bacterial proteins is a recently recognized pathogenic mechanism of bacteria that has a significant impact on host cell biology.…”