Helicobacter pylori CagA‐mediated IL‐8 induction in gastric epithelial cells is cholesterol‐dependent and requires the C‐terminal tyrosine phosphorylation‐containing domain

Upon infection of the gastric epithelial cells, the Helicobacter pylori cytotoxin‐associated gene A (CagA) virulence protein is injected into the epithelial cells via the type IV secretion system (TFSS), which is dependent on cholesterol. Translocated CagA is targeted by the membrane‐recruited c‐Src...

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Bibliographic Details
Published in:FEMS microbiology letters 2011-10, Vol.323 (2), p.155-163
Main Authors: Lai, Chih‐Ho, Wang, Hung‐Jung, Chang, Yun‐Chieh, Hsieh, Wan‐Chen, Lin, Hwai‐Jeng, Tang, Chih‐Hsin, Sheu, Jim Jinn‐Chyuan, Lin, Chun‐Jung, Yang, Mei‐Shiang, Tseng, Shu‐Fen, Wang, Wen‐Ching
Format: Article
Language:English
Subjects:
Antigens, Bacterial - immunology
Bacterial Proteins - immunology
Bacteriology
Biological and medical sciences
Cells, Cultured
cholesterol
Cholesterol - metabolism
cytotoxin‐associated gene A
Epithelial Cells - immunology
Epithelial Cells - microbiology
Fundamental and applied biological sciences. Psychology
H elicobacter pylori
Helicobacter pylori
Helicobacter pylori - immunology
Humans
Interleukin-8 - secretion
interleukin‐8
Microbiology
Miscellaneous
Protein Structure, Tertiary
Protein Transport
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Summary:Upon infection of the gastric epithelial cells, the Helicobacter pylori cytotoxin‐associated gene A (CagA) virulence protein is injected into the epithelial cells via the type IV secretion system (TFSS), which is dependent on cholesterol. Translocated CagA is targeted by the membrane‐recruited c‐Src family kinases in which a tyrosine residue in the Glu‐Pro‐Ile‐Tyr‐Ala (EPIYA)‐repeat region, which can be phosphorylated, induces cellular responses, including interleukin‐8 (IL‐8) secretion and hummingbird phenotype formation. In this study, we explored the role of EPIYA‐containing C‐terminal domain (CTD) in CagA tethering to the membrane lipid rafts and in IL‐8 activity. We found that disruption of the lipid rafts reduced the level of CagA translocation/phosphorylation as well as CagA‐mediated IL‐8 secretion. By CagA truncated mutagenesis, we identified that the CTD, rather than the N‐terminal domain, was responsible for CagA tethering to the plasma membrane and association with detergent‐resistant membranes, leading to CagA‐induced IL‐8 promoter activity. Our results suggest that CagA CTD‐containing EPIYAs directly interact with cholesterol‐rich microdomains that induce efficient IL‐8 secretion in the epithelial cells.
ISSN:0378-1097
1574-6968
DOI:10.1111/j.1574-6968.2011.02372.x