Exoenzyme S of Pseudomonas aeruginosa is not able to induce apoptosis when cells express activated proteins, such as Ras or protein kinase B/Akt.
Intracellular targeting of the Pseudomonas aeruginosa toxins, such as exoenzyme S (ExoS), cause cell death, as well as morphological and physiological changes in various tissue culture cells and animal models. In this report we have investigated the mechanism behind ExoS-mediated cell death. In order to address this issue, we have used cell lines expressing activated forms of various components of the Ras signalling pathway in order to evaluate the importance of the Ras pathway for viability and survival upon ExoS infection. Here we show that activated Ras is able to protect cells against cell death, regardless of whether it has been ADP-ribosylated by ExoS. Further, an activated form of protein kinase B (PKB)/Akt also leads to decreased level of cell death in response to ExoS infection, indicating that an important ExoS survival target is located upstream of Raf-1 and PKB/Akt. Moreover, we show that ExoS infection inhibits phosphorylation of FOXO3a, and induces caspase-3 activity, which are hallmarks for induction of cell death. In conclusion, we suggest that Ras proteins are an important cellular target for the P. aeruginosa toxin ExoS, which induces cell death during pathogenesis as a means of defending the bacterium against eukaryotic phagocytosis.
Jansson
Anna L
AL
Department of Medical Biosciences/Pathology, Umeå University, S-901 87, Umeå, Sweden.
Yasmin
Lubna
L
Warne
Patricia
P
Downward
Julian
J
Palmer
Ruth H
RH
Hallberg
Bengt
B
D036002:ADP Ribose Transferases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010587:Phagocytosis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D015398:Signal Transduction; D015011:Yersinia pseudotuberculosis / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000096:biosynthesis*
D001427:Bacterial Toxins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D036002:ADP Ribose Transferases; C444820:exoenzyme S; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D018631:ras Proteins