My laboratory studies how the bacterial pathogen Pseudomonas aeruginosa causes disease. In particular, we are focusing on the type III secretion system that allows P. aeruginosa to deliver protein toxins directly into the cytoplasm of targeted host cells. Secretion is triggered by cell contact. This mode of intoxication is therefore often referred to as contact-dependent secretion.
Our interest in type III secretion is two-fold. On the one hand, we are trying to elucidate in greater detail how the secretion apparatus functions mechanistically. This includes questions such as recognition of secretion substrates, how a hierarchy of secretion is imposed (e.g. components of the apparatus being secreted before effectors during assembly) and how triggering of secretion upon cell contact is achieved.
On the other hand, we are interested in the way expression of this complex machinery and its substrates is coordinated. We recently identified a negative regulator, ExsE, that is exported from the bacterial cell via the type III secretion machinery. Secretion of ExsE sets into motion a complex cascade of protein-protein interactions, which ultimately results in the activation of the transcriptional regulator ExsA. ExsA is the master regulator that is required for expression of type III secretion related structural genes and toxin genes. We are interested in testing this model of regulation in greater molecular detail and elucidating how global regulatory pathways impact on this regulation.
Model of type III secretion gene induction. When the secretion channel is closed, ExsE sequesters ExsC, which allows ExsD to bind ExsA and prevent transcription of the type III secretion genes (here represented by the exoS gene). Upon triggering of secretion, ExsE is exported via the type III secretion apparatus, which allows ExsC to bind ExsD, thereby activating ExsA to promote transcription. (E… ExsE, V… PcrV)
Selected Publications
Rietsch A. and Mekalanos, J.J, (2006) Metabolic Regulation of Type III Secretion Gene Expression in Pseudomonas aeruginosa, Mol. Micro. 59(3):807-820. [PubMed]
Rietsch A., Vallet-Gely I., Dove S.L. and Mekalanos, J.J., (2005) ExsE, a secreted regulator of type III secretion genes in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. U.S.A. 102(22):8006-11. [PubMed]
Rietsch A., Wolfgang M.C., Mekalanos J.J. (2004) Effect of metabolic imbalance on expression of type III secretion genes in Pseudomonas aeruginosa. Infect. Immun. 72(3):1383-90. [PubMed]
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