Integrins Lock and Load

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

Helicobacter pylori is a Gram-negative bacterium associated with stomach ulcers and gastric cancer. As Hauck discusses in commentary, H. pylori injects its virulence factors, which include the oncoprotein cytotoxin-associated gene A (CagA), into gastric epithelial cells using a multisubunit complex called the type-IV secretion pilus. CagA is then tyrosine-phosphorylated by Src, leading to restructuring of the actin cytoskeleton and the elongation of infected cells. To identify the host receptor targeted by H. pylori, Kwok et al. used confocal microscopy to determine that phosphorylated CagA was predominantly localized to focal adhesions in infected human gastric adenocarcinoma (AGS) cells. Focal adhesions are sites where clusters of integrins, heterodimeric adhesion receptors, anchor the cell to the extracellular matrix. The addition of blocking antibodies against the integrins ₅ and ₁ inhibited H. pylori-induced phosphorylation of CagA in AGS cells. The authors identified CagL as the only protein associated with the type-IV secretion system that contained the arginine-glycine-aspartate (RGD) motif that is required to bind to integrins. Microscopic analysis showed that CagL was localized to the bacterial pilus during infection of AGS cells. H. pylori that expressed CagL proteins with mutated RGD motifs that could not bind to integrins failed to translocate CagA into AGS cells. Western blotting showed that the tyrosine kinases focal adhesion kinase (FAK) and Src were phosphorylated in AGS cells infected with H. pylori that expressed wild-type CagL, but not with H. pylori that expressed a CagL with a mutated RGD motif. These data uncover a new role for integrins in microbial pathogenesis and suggest CagL as a potential drug target in the treatment of H. pylori infections.

T. Kwok, D. Zabler, S. Urman, M. Rohde, R. Hartig, S. Wessler, R. Misselwitz, J. Berger, N. Sewald, W. König, S. Backert, Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449, 862-866 (2007). [PubMed]

C. R. Hauck, Preparing the shot. Nature 449, 798-799 (2007). [PubMed]

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