1. Department of Medical Microbiology, and,
2. Department of Immunology, Otto von Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany
3. Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstrasse 25, D-33615 Bielefeld, Germany
4. Helmholtz Center for Infection Research, Department of Microbial Pathogenesis, Inhoffen Strasse 7, D-38124 Braunschweig, Germany
5. Paul Ehrlich Institute, Paul-Ehrlich-Strasse 51-59, D-63225 Langen, Germany
6. Max Delbrück Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany
7. Max Planck Institute for Developmental Biology, Spemannstrasse 35, D-72076 Tübingen, Germany
8. Present addresses: University of Zürich, Institute of Medical Virology, Gloriastrasse 30/32, CH-8006 Zürich, Switzerland (T.K.); Institute for Immuno Genetics, Charité University Clinics Berlin, Humboldt University Berlin, Spandauer Damm 130, D-14050 Berlin, Germany (R.M.).

Correspondence to: Steffen Backert¹ Correspondence and requests for materials should be addressed to S.B. (Email: Steffen.Backert@med.ovgu.de).

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 ₅₁ 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.

1. Department of Medical Microbiology, and,
2. Department of Immunology, Otto von Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany
3. Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstrasse 25, D-33615 Bielefeld, Germany
4. Helmholtz Center for Infection Research, Department of Microbial Pathogenesis, Inhoffen Strasse 7, D-38124 Braunschweig, Germany
5. Paul Ehrlich Institute, Paul-Ehrlich-Strasse 51-59, D-63225 Langen, Germany
6. Max Delbrück Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany
7. Max Planck Institute for Developmental Biology, Spemannstrasse 35, D-72076 Tübingen, Germany
8. Present addresses: University of Zürich, Institute of Medical Virology, Gloriastrasse 30/32, CH-8006 Zürich, Switzerland (T.K.); Institute for Immuno Genetics, Charité University Clinics Berlin, Humboldt University Berlin, Spandauer Damm 130, D-14050 Berlin, Germany (R.M.).

Correspondence to: Steffen Backert¹ Correspondence and requests for materials should be addressed to S.B. (Email: Steffen.Backert@med.ovgu.de).

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