Translocation of Helicobacter pylori CagA into Gastric Epithelial Cells by Type IV Secretion

Abstract

The Gram-negative bacterium Helicobacter pylori is a causative agent of gastritis and peptic ulcer disease in humans. Strains producing the CagA antigen (cagA(+)) induce strong gastric inflammation and are strongly associated with gastric adenocarcinoma and MALT lymphoma. We show here that such strains translocate the bacterial protein CagA into gastric epithelial cells by a type IV secretion system, encoded by the cag pathogenicity island. CagA is tyrosine-phosphorylated and induces changes in the tyrosine phosphorylation state of distinct cellular proteins. Modulation of host cells by bacterial protein translocation adds a new dimension to the chronic Helicobacter infection with yet unknown consequences.

The versatile bacterial type IV secretion systems

“…In parallel, studies by several laboratories are generating extensive information about the cellular consequences of CagA translocation. On transfer, CagA localizes on the inner surface of the plasma membrane where it interacts with and is phosphorylated by the Src family of protein tyrosine kinases, such as c-Src [84][85][86][87][88][89][90][91] . The CagA phosphorylation sites have been mapped to the so-called EPIYA motifs that share homology with c-Src consensus phosphorylation sites and are present in variable numbers in the carboxy-terminal half of the protein 89,91 .…”

Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility

“…Cells were seeded in tissue culture plates for 48 h before infection and serum-starved for 16 h. Phase-contrast microscopy was performed using an inverted microscope (model TS 100, INTAS). H. pylori strains P1, P12 and Hp26695 and their isogenic mutants DCagA and DPAI have been described elsewhere (Schmitt and Haas 1994;Corthesy-Theulaz et al, 1996;Tomb et al, 1997;Odenbreit et al, 2000;Wessler et al, 2000). Bacteria were cultured on agar plates containing 10% horse serum under microaerophilic conditions at 371C for 48 h. For infection, bacteria were harvested in phosphate-buffered saline (PBS), pH 7.4 and added to the host cells at a multiplicity of infection (MOI) of 100 for the indicated periods of time.…”

“…Its genome contains a cagpathogenicity island (cagPAI), encoding proteins for a specialized type IV secretion system (T4SS), which injects virulence factors directly into the host cytoplasm of infected epithelial cells. So far, peptidoglycans (Viala et al, 2004) and the CagA protein (Asahi et al, 2000;Backert et al, 2000;Odenbreit et al, 2000;Stein et al, 2000) are known to translocate into the infected epithelial host cell. Translocated CagA induces cellular processes, which lead to stimulation of cell dissemination followed by cell motility, and invasive growth in gastric epithelial cells (Segal et al, 1999;Bagnoli et al, 2005).…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…Following the attachment of cagA-positive H. pylori to the surface of gastric epithelial cells, CagA is delivered from the bacterium into the cytoplasm of host cells through the type IV secretion system (Segal et al, 1999;Asahi et al, 2000;Backert et al, 2000;Odenbreit et al, 2000;Stein et al, 2000). This process is mediated at least partly through an interaction of H. pylori CagL with integrins (Kwok et al, 2007).…”