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Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion.
Hammond CE, Beeson C, Suarez G, Peek RM, Backert S, Smolka AJ
(2015) Am J Physiol Gastrointest Liver Physiol 309: G193-201
MeSH Terms: Achlorhydria, Antigens, Bacterial, Bacterial Proteins, Cells, Cultured, Epithelial Cells, Gastric Acid, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Interleukin-8, NF-kappa B, Promoter Regions, Genetic, Proton Pumps, Signal Transduction, Sodium-Potassium-Exchanging ATPase, Virulence Factors
Show Abstract · Added February 5, 2016
Acute Helicobacter pylori infection of gastric epithelial cells and human gastric biopsies represses H,K-ATPase α subunit (HKα) gene expression and inhibits acid secretion, causing transient hypochlorhydria and supporting gastric H. pylori colonization. Infection by H. pylori strains deficient in the cag pathogenicity island (cag PAI) genes cagL, cagE, or cagM, which do not transfer CagA into host cells or induce interleukin-8 secretion, does not inhibit HKα expression, nor does a cagA-deficient strain that induces IL-8. To test the hypothesis that virulence factors other than those mediating CagA translocation or IL-8 induction participate in HKα repression by activating NF-κB, AGS cells transfected with HKα promoter-Luc reporter constructs containing an intact or mutated NF-κB binding site were infected with wild-type H. pylori strain 7.13, isogenic mutants lacking cag PAI genes responsible for CagA translocation and/or IL-8 induction (cagA, cagζ, cagε, cagZ, and cagβ), or deficient in genes encoding two peptidoglycan hydrolases (slt and cagγ). H. pylori-induced AGS cell HKα promoter activities, translocated CagA, and IL-8 secretion were measured by luminometry, immunoblotting, and ELISA, respectively. Human gastric biopsy acid secretion was measured by microphysiometry. Taken together, the data showed that HKα repression is independent of IL-8 expression, and that CagA translocation together with H. pylori transglycosylases encoded by slt and cagγ participate in NF-κB-dependent HKα repression and acid inhibition. The findings are significant because H. pylori factors other than CagA and IL-8 secretion are now implicated in transient hypochlorhydria which facilitates gastric colonization and potential triggering of epithelial progression to neoplasia.
Copyright © 2015 the American Physiological Society.
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17 MeSH Terms
Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa.
Saha A, Hammond CE, Beeson C, Peek RM, Smolka AJ
(2010) Gut 59: 874-81
MeSH Terms: Adult, Antigens, Bacterial, Bacterial Proteins, Gastric Acid, Gastric Mucosa, Genes, Bacterial, H(+)-K(+)-Exchanging ATPase, Helicobacter Infections, Helicobacter pylori, Humans, Middle Aged, Promoter Regions, Genetic, Proton Pumps, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Tissue Culture Techniques, Tumor Cells, Cultured, Virulence, Young Adult
Show Abstract · Added March 5, 2014
BACKGROUND AND AIMS - Helicobacter pylori infection of gastric mucosa causes gastritis and transient hypochlorhydria, which may provoke emergence of a mucosal precancer phenotype; H pylori strains containing a cag pathogenicity island (PAI) augment cancer risk. Acid secretion is mediated by the catalytic alpha subunit of parietal cell H,K-ATPase (HKalpha). In AGS gastric epithelial cells, H pylori induces nuclear factor-kappaB (NF-kappaB) binding to and repression of transfected HKalpha promoter activity. This study sought to identify bacterial genes involved in HKalpha repression and to assess their impact on acid secretion.
METHODS AND RESULTS - AGS cells transfected with an HKalpha promoter construct or human gastric body biopsies were infected with wild-type (wt) or isogenic mutant (IM) H pylori strains. AGS cell HKalpha promoter activity, and biopsy HKalpha mRNA, protein and H(+) secretory activity were measured by luminometry, reverse transcription-PCR, immunoblotting and extracellular acidification, respectively. Wt H pylori and DeltavacA, DeltaureA, Deltaslt and DeltaflaA IM strains repressed HKalpha promoter activity by approximately 50%, a DeltacagA IM strain repressed HKalpha by approximately 33%, and DeltacagE, DeltacagM and DeltacagL IM strains elicited no HKalpha repression. Wt H pylori-infected biopsies had markedly reduced HKalpha mRNA and protein compared with IM strain infections or mock-infected controls. Histamine-stimulated, SCH28080-sensitive biopsy acid secretion was significantly inhibited by wt but not by DeltacagL IM H pylori infection compared with vehicle-only controls.
CONCLUSIONS - It is concluded that H pylori cag PAI gene products CagE, CagM, CagL and, possibly, CagA are mechanistically involved in repression of HKalpha transcription. Further, acute H pylori infection of human gastric mucosa downregulates parietal cell H,K-ATPase expression, significantly inhibiting acid secretion.
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19 MeSH Terms
Structural changes in bacteriorhodopsin during ion transport at 2 angstrom resolution.
Luecke H, Schobert B, Richter HT, Cartailler JP, Lanyi JK
(1999) Science 286: 255-61
MeSH Terms: Bacteriorhodopsins, Binding Sites, Crystallography, X-Ray, Cytoplasm, Hydrogen Bonding, Hydrogen-Ion Concentration, Ion Transport, Isomerism, Light, Models, Molecular, Photolysis, Photons, Point Mutation, Protein Conformation, Protein Structure, Secondary, Proton Pumps, Protons, Retinaldehyde, Schiff Bases, Thermodynamics, Water
Show Abstract · Added May 7, 2010
Crystal structures of the Asp96 to Asn mutant of the light-driven proton pump bacteriorhodopsin and its M photointermediate produced by illumination at ambient temperature have been determined to 1.8 and 2.0 angstroms resolution, respectively. The trapped photoproduct corresponds to the late M state in the transport cycle-that is, after proton transfer to Asp85 and release of a proton to the extracellular membrane surface, but before reprotonation of the deprotonated retinal Schiff base. Its density map describes displacements of side chains near the retinal induced by its photoisomerization to 13-cis,15-anti and an extensive rearrangement of the three-dimensional network of hydrogen-bonded residues and bound water that accounts for the changed pKa values (where Ka is the acid constant) of the Schiff base and Asp85. The structural changes detected suggest the means for conserving energy at the active site and for ensuring the directionality of proton translocation.
1 Communities
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21 MeSH Terms