Escherichia coli enterotoxin B subunit triggers apoptosis of CD8(+) T cells by activating transcription factor c-myc.
Heat-labile enterotoxin from enterotoxinogenic Escherichia coli is not only an important cause of diarrhea in humans and domestic animals but also possesses potent immunomodulatory properties. Recently, the nontoxic, receptor-binding B subunit of heat-labile enterotoxin (EtxB) was found to induce the selective death of CD8(+) T cells, suggesting that EtxB may trigger activation of proapoptotic signaling pathways. Here we show that EtxB treatment of CD8(+) T cells but not of CD4(+) T cells triggers the specific up-regulation of the transcription factor c-myc, implicated in the control of cell proliferation, differentiation, and death. A concomitant elevation in Myc protein levels was also evident, with peak expression occurring 4 h posttreatment. Preincubation with c-myc antisense oligodeoxynucleotides demonstrated that Myc expression was necessary for EtxB-mediated apoptosis. Myc activation was also associated with an increase of IkappaBalpha turnover, suggesting that elevated Myc expression may be dependent on NF-kappaB. When CD8(+) T cells were pretreated with inhibitors of IkappaBalpha turnover and NF-kappaB translocation, this resulted in a marked reduction in both EtxB-induced apoptosis and Myc expression. Further, a non-receptor-binding mutant of EtxB, EtxB(G33D), was shown to lack the capacity to activate Myc transcription. These findings provide further evidence that EtxB is a signaling molecule that triggers activation of transcription factors involved in cell survival.
Soriani
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M
Department of Pathology and Microbiology, University of Bristol, Bristol, BS8 1TD, United Kingdom.
Williams
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NA
Hirst
T R
TR
D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D029968:Escherichia coli Proteins; D020672:I-kappa B Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D020319:Oligodeoxyribonucleotides, Antisense; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D015533:Transcriptional Activation
D001427:Bacterial Toxins; D004268:DNA-Binding Proteins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D020319:Oligodeoxyribonucleotides, Antisense; D011500:Protein Synthesis Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D000072000:NF-KappaB Inhibitor alpha; D014108:Tosylphenylalanyl Chloromethyl Ketone; C027538:heat-labile enterotoxin, E coli