title: Bcl-2 regulates the onset of shiga toxin 1-induced apoptosis in THP-1 cells.
abstract: Shiga toxins (Stxs), which are proteins expressed by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli, are potent protein synthesis inhibitors. Stx-producing organisms cause bloody diarrhea with the potential to progress to acute renal failure and central nervous system complications. Studies using animal models of these diseases have shown that Stxs are major virulence factors, and purified toxins have been shown to be capable of killing many types of cells in vitro. We showed that Stx type 1 (Stx1) rapidly induced apoptosis in undifferentiated, monocytic THP-1 cells through a mechanism involving the endoplasmic reticulum (ER) stress response. Rapid apoptosis correlated with increased expression of C/EBP homologous protein (CHOP), TRAIL, and DR5, while expression of the antiapoptotic factor Bcl-2 was downregulated. Stx1 treatment of differentiated, macrophage-like THP-1 cells was associated with cytokine production and delayed apoptosis. The mechanisms contributing to cell maturation-dependent differences in responses to Stx1 are unknown. We show here that in macrophage-like cells, Stx1 activated the proximal ER stress sensors RNA-dependent protein kinase-like ER kinase and inositol-requiring ER signal kinase 1alpha but did not activate activating transcription factor 6. Proapoptotic signaling pathways mediated by CHOP and by Bax and Bak were activated by Stx1. However, the toxin also activated prosurvival signaling through increased expression, mitochondrial translocation, and alternative phosphorylation of Bcl-2.
authors.affiliation: Department of Microbial and Molecular Pathogenesis, Texas A&M University System Health Science Center, College Station, Texas 77843-1114, USA.
authors.forename: Moo-Seung
authors.initials: MS
authors.lastname: Lee
authors.forename: Rama P
authors.initials: RP
authors.lastname: Cherla
authors.forename: Dinorah
authors.initials: D
authors.lastname: Leyva-Illades
authors.forename: Vernon L
authors.initials: VL
authors.lastname: Tesh
mesh_terms: D051702:Activating Transcription Factor 6 / Q000096:biosynthesis; D017209:Apoptosis; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004722:Endoribonucleases / Q000096:biosynthesis; D004926:Escherichia coli / Q000472:pathogenicity*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects* / Q000382:microbiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D022622:Shiga Toxin 1 / Q000633:toxicity*; D012762:Shigella dysenteriae / Q000472:pathogenicity*; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D019892:eIF-2 Kinase / Q000096:biosynthesis
chemical_list: D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D022622:Shiga Toxin 1; D051742:Transcription Factor CHOP; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C494772:BAK1 protein, human; C494826:BAX protein, human; C497249:DDIT3 protein, human; C403982:ERN2 protein, human