The secreted peptidyl prolyl cis,trans-isomerase HP0175 of Helicobacter pylori induces apoptosis of gastric epithelial cells in a TLR4- and apoptosis signal-regulating kinase 1-dependent manner.
Apoptosis contributes to the pathology of gastric epithelial cell damage that characterizes Helicobacter pylori infection. The secreted peptidyl prolyl cis, trans-isomerase of H. pylori, HP0175 executed apoptosis of the gastric epithelial cell line AGS in a dose- and time-dependent manner. The effect of HP0175 was confirmed by generating an isogenic mutant of H. pylori disrupted in the HP0175 gene. The apoptosis-inducing ability of this mutant was impaired compared with that of the wild type. The effect of HP0175 was mediated through TLR4. Preincubation of the gastric epithelial cell line AGS with anti-TLR4 mAb inhibited apoptosis induced by HP0175. Downstream of TLR4, apoptosis signal-regulating kinase 1 activated MAPK p38, leading to the caspase 8-dependent cleavage of Bid, its translocation to the mitochondria, mitochondrial pore formation, cytochrome c release, and activation of caspases 9 and 3. We show for the first time that a secreted bacterial Ag with peptidyl prolyl cis,trans-isomerase activity signals through TLR4, and that this Ag executes gastric epithelial cell apoptosis through a signaling pathway in which TLR4 and apoptosis signal-regulating kinase 1 are central players.
Basak
Chaitali
C
Department of Chemistry, Bose Institute, Kolkata, India.
Pathak
Sushil Kumar
SK
Bhattacharyya
Asima
A
Pathak
Shresh
S
Basu
Joyoti
J
Kundu
Manikuntala
M
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000235:genetics; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000235:genetics; D005753:Gastric Mucosa / Q000166:cytology / Q000201:enzymology* / Q000382:microbiology*; D016480:Helicobacter pylori / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D006639:Histidine / Q000737:chemistry; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology*; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D010539:Permeability; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D006639:Histidine; D045304:Cytochromes c; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020169:Caspases; D019696:Peptidylprolyl Isomerase