Small GTPase signalling networks utilised by Salmonella Thyphimurium virulence factors

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Pathogenic bacteria frequently manipulate eukaryotic host cells by targeting actin cytoskeletal turnover. This is achieved e.g. by manipulating or mimicking the regulators controlling actin dynamics such as members of the Rho family of small GTPases. Rho-GTPases serve as molecular switches that – while cycling - turn entire signalling pathways, on and off, like those driving actin remodelling. Salmonella has evolved multiple strategies to affect these signals e.g. through its bacterial GEF-mimicks SopE/E2 or indirectly by phospholipid-modifying enzymes such as SopB. Salmonella harbours two more putative bacterial GEFs, SifA and SifB, which belong to a novel and growing group termed WxxxE-family. Interestingly, bacterial virulence factors have also emerged to bind to host cell signalling adaptors, underscoring that these factors do not simply elicit global signal pathways, but assemble larger complexes guiding the signal to a specific destination. It is the aim of this proposal to uncover how virulence factors of Salmonella that effect small GTPase activation accomplish specificity by engaging in signalling complexes. To achieve this, we have begun to identify interactors using yeast two hybrid screening. Potential candidates are validated and tested for their influence on virulence factor-elicited signalling using state of the art biochemistry, cell biology and imaging. Finally, crystal structures of these complexes will disclose the molecular details of these intricate host-pathogen interactions.