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PMID:21482684
| Citation |
Radin, JN, González-Rivera, C, Ivie, SE, McClain, MS and Cover, TL (2011) Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells. Infect. Immun. 79:2535-43 |
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| Abstract |
Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors of H. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augments H. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration. |
| Links |
PubMed PMC3191986 Online version:10.1128/IAI.01370-10 |
| Keywords |
Adenosine Triphosphate/metabolism; Bacterial Proteins/genetics; Bacterial Proteins/physiology; Bacterial Toxins/metabolism; Blotting, Western; Caspases/metabolism; Cell Death; Cell Line; Cell Line, Tumor; Epithelial Cells/microbiology; Epithelial Cells/pathology; Gastric Mucosa/microbiology; Gastric Mucosa/pathology; Gastritis/microbiology; HMGB1 Protein/metabolism; Helicobacter pylori/metabolism; Helicobacter pylori/pathogenicity; Humans; Ion Channels; L-Lactate Dehydrogenase/metabolism; Necrosis; Peptic Ulcer/microbiology; Poly(ADP-ribose) Polymerases/metabolism; Stomach Neoplasms/microbiology; Virulence Factors/physiology |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0012501: programmed cell death |
ECO:0000315: |
P |
Figure 1 shows that VacA increases the death of gastric epithelial cells compared to the nonfunctional mutant both when the cells are incubated with supernatant from both H.pylori strains or when incubated with the purified VacA or mutant VacA proteins. Figure 2 shows that VacA causes the cells to swell, implying necrosis and not apoptosis. Figure 8 shows that the pathway in which VacA causes cell death is caspase-independent. |
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Notes
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