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Infection and Immunity, June 2003, p. 3361-3370, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3361-3370.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

c-Jun NH2-Terminal Kinase-Mediated Signaling Is Essential for Pseudomonas aeruginosa ExoS-Induced Apoptosis

Jinghua Jia,1 Mounia Alaoui-El-Azher,1 Marie Chow,2 Timothy C. Chambers,3 Henry Baker,1 and Shouguang Jin1*

Department of Molecular Genetics and Microbiology, University of Florida School of Medicine, Gainesville, Florida 32610,1 Department of Microbiology and Immunology,2 Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 722053

Received 26 December 2002/ Returned for modification 31 January 2003/ Accepted 12 March 2003

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 NH2-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.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, P. O. Box 100266, University of Florida, Gainesville, FL 32610. Phone: (352) 392-8323. Fax: (352) 392-3133. E-mail: sjin{at}mgm.ufl.edu.

Editor: F. C. Fang

Infection and Immunity, June 2003, p. 3361-3370, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3361-3370.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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