Pseudomonas aeruginosa ExoT Induces Atypical Anoikis Apoptosis in Target Host Cells by Transforming Crk Adaptor Protein into a Cytotoxin

Previously, we demonstrated that Pseudomonas aeruginosa ExoT induces potent apoptosis in host epithelial cells in a manner that primarily depends on its ADP-ribosyltransferase domain (ADPRT) activity. However, the mechanism underlying ExoT/ADPRT-induced apoptosis remains undetermined. We now report that ExoT/ADPRT disrupts focal adhesion sites, activates p38β and JNK, and interferes with integrin-mediated survival signaling; causing atypical anoikis. We show that ExoT/ADPRT-induced anoikis is mediated by the Crk adaptor protein. We found that Crk^-/- knockout cells are significantly more resistant to ExoT-induced apoptosis, while Crk^-/- cells complemented with Crk are rendered sensitive to ExoT-induced apoptosis. Moreover, a dominant negative (DN) mutant form of Crk phenocopies ExoT-induced apoptosis both kinetically and mechanistically. Crk is generally believed to be a component of focal adhesion (FA) and its role in cellular survival remains controversial in that it has been found to be either pro-survival or pro-apoptosis. Our data demonstrate that although Crk is recruited to FA sites, its function is likely not required for FA assembly or for survival per se. However, when modified by ExoT or by mutagenesis, it can be transformed into a cytotoxin that induces anoikis by disrupting FA sites and interfering with integrin survival signaling. To our knowledge, this is the first example whereby a bacterial toxin exerts its cytotoxicity by subverting the function of an innocuous host cellular protein and turning it against the host cell.     

Wichtigere neue Funde von Phanerogamen in Nordtirol

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Recurrence of the unfit

Domination among strategies in an evolutionary game implies that the geometric mean of the frequencies of certain strategies—the unfit—approaches zero. However, as we show by example no one strategy need be eliminated in the limit.     

Über eigenartige organische Membraneinschlüsse in der Epidermis vonPortulaca Gilliesii Hook

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Gagea Szepusiana mihi

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Über den Hausschwamm und seine nächsten Verwandten

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Beitrag zur Kenntnis der Flora von West-Bosnien

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Harn-steroidprofile hirsuter frauen

Urine steroid profiles of hirsute womenSteroid profiles of women suffering from idiopathic hirsutism show in more than 50% of the cases a 10–100 fold increase in the excretion of dehydroepiandrosterone (DHEA) compared with normal values.The excretion of DHEA was reduced much more than that of other 17-ketosteroids if the adrenals (NNR) were suppressed by dexamethasone (DXM). Within one week they reached values at the compound noise level of the gas chromatograms. If the ovaries were stimulated with human chorionic gonadotropin during continued suppression of the NNR with DXM no increase of DHEA could be detected.