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Helicobacter exploits integrin for type IV secretion and kinase activation

Abstract

Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin α5β1 receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori-induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling.

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Figure 1: Phosphorylated CagA co-localizes with focal adhesion proteins during infection with H. pylori , and integrin β 1 is required for type-IV secretion of CagA into target cells.
Figure 2: The surface protein CagL associates with the type-IV secretion pilus surface during infection.
Figure 3: H. pylori CagL and its RGD motif are essential for type-IV secretion of CagA.
Figure 4: RGD-dependent interaction of CagL with integrin α 5 β 1.
Figure 5: The RGD motif of CagL is crucial for activation of FAK and Src tyrosine kinases.
Figure 6: Three-step model for the activation of the H. pylori type-IV secretion system and phosphorylation of CagA through interaction of CagL with integrin.

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Acknowledgements

We thank I. Schleicher, D. Schmidt and N. Tegtmeyer for technical assistance, and S. Johansson and R. Faessler for providing GD25 cells. U. Strijowski synthesized the peptides. This work was supported through Magdeburger-Forschungsverbund and a DFG priority program grant.

Author Contributions T.K. purified CagL and performed cell binding studies, flow cytometry and integrin expression assays; S.B. designed the concept, performed the cloning work, constructed H. pylori mutants and supervised the project; D.Z. did the infections experiments, cell fractionation and western blotting; S.U. and N.S. performed the Biacore binding studies and designed the synthetic CagL peptides; M.R. and J.B. performed the FESEM studies; R.H. and S.W. conducted the immunofluorescence experiments; R.M. did the CD analyses and W.K. provided materials; T.K. and S.B. wrote the paper.

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Correspondence to Steffen Backert.

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Kwok, T., Zabler, D., Urman, S. et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449, 862–866 (2007). https://doi.org/10.1038/nature06187

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