Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells.
Shiga toxins (Stxs) expressed by the enteric pathogens Shigella dysenteriae 1 and enterohaemorrhagic Escherichia coli are potent protein synthesis inhibitors. Shiga toxins have also been shown to induce apoptosis in epithelial, endothelial and monocytic cells. The precise relationship between protein synthesis inhibition and induction of apoptosis is not known. We show that stimulation of the myelogenous leukaemia cell line THP-1 with purified Stx1 induced the endoplasmic reticulum (ER) stress response. Stx1 treatment increased activation of the ER stress sensors IRE1, PERK and ATF6. Toxin treatment increased expression of the transcriptional regulator CHOP and the death domain-containing receptor DR5 at mRNA and protein levels. Following Stx1 intoxication, levels of the survival factor Bcl-2 decreased, while secretion of the death-inducing ligand TRAIL increased. Stx1 enzymatic activity was required for optimal activation of PERK and ATF6, but not IRE1. ER stress elicited by Stx1 increased the release of Ca(2+) from ER stores and the activation of the protease calpain. Inhibition of calpain activity led to reductions in Stx1-induced cleavage of procaspase-8 and apoptosis. Collectively, these data suggest that Shiga toxins trigger monocytic cell apoptosis through the ER stress response, the increased expression of DR5 and TRAIL, and activation of caspase-8 via a calpain-dependent mechanism.
Lee
Sang-Yun
SY
Department of Microbial and Molecular Pathogenesis, Texas A&M University Health Science Center, College Station, Texas 77843-1114, USA.
Lee
Moo-Seung
MS
Cherla
Rama P
RP
Tesh
Vernon L
VL
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism; D004926:Escherichia coli / Q000472:pathogenicity*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022622:Shiga Toxin 1 / Q000302:isolation & purification / Q000633:toxicity*; D012762:Shigella dysenteriae / Q000472:pathogenicity*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051742:Transcription Factor CHOP; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D002118:Calcium; D002154:Calpain; D053181:Caspase 8; D004722:Endoribonucleases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D022622:Shiga Toxin 1; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C497249:DDIT3 protein, human; C505653:TNFSF10 protein, human; C403982:ERN2 protein, human