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

Chih Ho Lai, Hung Jung Wang, Yun Chieh Chang, Wan Chen Hsieh, Hwai Jeng Lin, Chih Hsin Tang, Jim Jinn Chyuan Sheu, Chun Jung Lin, Mei Shiang Yang, Shu Fen Tseng, Wen Ching Wang

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)155-163
Number of pages9
JournalFEMS Microbiology Letters
Volume323
Issue number2
DOIs
Publication statusPublished - Oct 2011

Keywords

  • Cholesterol
  • Cytotoxin-associated gene A
  • H elicobacter pylori
  • Interleukin-8

ASJC Scopus subject areas

  • Microbiology
  • Genetics
  • Molecular Biology

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