title: c-Jun NH2-terminal kinase-mediated signaling is essential for Pseudomonas aeruginosa ExoS-induced apoptosis.
abstract: As an opportunistic bacterial pathogen, Pseudomonas aeruginosa mainly affects immunocompromised individuals as well as patients with cystic fibrosis. In a previous study, we showed that ExoS of P. aeruginosa, when injected into host cells through a type III secretion apparatus, functions as an effector molecule to trigger apoptosis in various tissue culture cells. Here, we show that injection of the ExoS into HeLa cells activates c-Jun NH(2)-terminal kinase (JNK) phosphorylation while shutting down ERK1/2 and p38 phosphorylation. Inhibiting JNK activation by expression of a dominant negative JNK1 or with a specific JNK inhibitor abolishes ExoS-triggered apoptosis, demonstrating the requirement for JNK-mediated signaling. Following JNK phosphorylation, cytochrome c is released into the cytosol, leading to the activation of caspase 9 and eventually caspase 3. Although c-Jun phosphorylation is also observed as a result of JNK activation, ongoing host protein synthesis is not essential for the apoptotic induction, suggesting that c-Jun- or other AP-1-driven activation of gene expression is dispensable in this process. Therefore, ExoS has opposing effects on different cellular pathways that regulate apoptosis: it shuts down host cell survival signal pathways by inhibiting ERK1/2 and p38 activation, and it activates proapoptotic pathways through activation of JNK1/2 leading ultimately to cytochrome c release and activation of caspases. These results highlight the modulation of host cell signaling by the type III secretion system during interaction between P. aeruginosa and host cells.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida School of Medicine, Gainesville 32610, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Jia
authors.forename: Mounia
authors.initials: M
authors.lastname: Alaoui-El-Azher
authors.forename: Marie
authors.initials: M
authors.lastname: Chow
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Chambers
authors.forename: Henry
authors.initials: H
authors.lastname: Baker
authors.forename: Shouguang
authors.initials: S
authors.lastname: Jin
mesh_terms: D036002:ADP Ribose Transferases / Q000502:physiology*; D017209:Apoptosis; D001427:Bacterial Toxins; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D001427:Bacterial Toxins; D003574:Cytochrome c Group; D036002:ADP Ribose Transferases; C444820:exoenzyme S; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases