Functional role of integrin alpha5betha1 and the Helicobacter pylori CagL protein in type IV secretion and signal transduction

• Applicant: Professor Dr. Steffen Backert
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2008 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 76899855

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. Virulent H. pylori express a type-IV secretion pilus that injects the CagA protein, which then becomes tyrosinephosphorylated by Src family kinases. We have recently identified integrin α5β1 as the host cell receptor involved in type-IV secretion with the H. pylori CagL protein as ligand (Kwok et al. 2007, Nature 449, 862-866). We have shown that CagL is a novel specialised adhesin which is targeted to the pilus surface, where it binds to and activates integrin α5β1 through an RGD motif. This interaction triggered CagA delivery into target cells as well as activation of focal adhesion kinase FAK and Src which is an elegant mechanism for the bacteria to ensure phosphorylation of translocated CagA directly at the injection site. With this project, we aim to further contribute to the understanding of the mechanism underlying the receptor-dependent type-IV secretion induced by H. pylori. In particular, we would like to investigate the role of CagL in binding to integrin α5β1 with emphasis on how this interaction highjacks cellular signaling pathways. The role of CagL in the specific host cell responses such as the induction of membrane dynamics for injection of effector proteins as well as nuclear responses will be examined in detail. We focus on the Cag>integrin α5β1>FAK>Src and other pathways. This approach will allow us to reconstruct the sequence of events occurring at the pathogen–host cell interface, and to identify novel key pathogenicity determinants. Our findings will provide important insights into the role of integrins in H. pylori-induced pathogenesis.

• DFG Programme: Research Grants