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Functional characterization of ExoS, its activation and the functional effects of ExoS on cell signalling in vivo.

Research project Why is ExoS a killer?

Project overview

Project period:

2012-09-05 2012-12-31

Funding

Finansår , 2012, 2013, 2014, 2015

huvudman: Bengt Hallberg, finansiar: Barncancerfonden, y2012: 600, y2013: 600, y2014: 600, y2015: ,

huvudman: Bengt Hallberg, finansiar: Barncancerfonden, y2012: 360, y2013: 360, y2014: 360, y2015: 360,

huvudman: Bengt Hallberg, finansiar: VR-MH, y2012: 325, y2013: , y2014: , y2015: ,

huvudman: Bengt Hallberg, finansiar: Cancerfonden, y2012: 600, y2013: , y2014: , y2015: ,

Participating departments and units at Umeå University

Department of Molecular Biology, Faculty of Science and Technology

Research area

Biological sciences, Molecular biology and genetics

Project description



P. aeruginosa is an opportunistic pathogen that causes infections in immuno-compromised individuals and cause infections due to and arsenal of secreted virulence factor. Some virulence factors are translocated to the cell via a type III secretion system, such ExoS. ExoS is a bifunctional toxin with a C-terminal ADP-ribosylation activity, which modify activities of the Ras superfamily. The GAP domain of ExoS abrogates the activation of RhoA, Cdc42 and Rap1. The eukaryotic 14-3-3 proteins are necessary for the activity of ExoS. The interaction between 14-3-3 and ExoS occurs in a novel phosphorylation independent manner.

We will use immunohistochemistry and biochemical analysis, such as pull-down-, live/dead-, GAP-, ADP-ribosylation-assays using specific downstream substrate target proteins and site-specific mutagenesis on cells infected with ExoS. Further, structural crystal analysis is employed, followed by real life analysis to evaluate the pathogenesis in a mouse model of acute pneumonia.

Significance; the overall aim of this application is to increase our understanding of P. aeruginosa infection at a functional molecular level with respect to the critical bacterial toxin ExoS. This knowledge can then form the basis for new strategies of therapy and treatment of P. aeruginosa infections.