title: Shiga toxins induce autophagic cell death in intestinal epithelial cells via the endoplasmic reticulum stress pathway.
abstract: Shiga toxins (Stxs) are a family of cytotoxic proteins that lead to the development of bloody diarrhea, hemolytic-uremic syndrome, and central nervous system complications caused by bacteria such as S. dysenteriae, E. coli O157:H7 and E. coli O104:H4. Increasing evidence indicates that macroautophagy (autophagy) is a key factor in the cell death induced by Stxs. However, the associated mechanisms are not yet clear. This study showed that Stx2 induces autophagic cell death in Caco-2 cells, a cultured line model of human enterocytes. Inhibition of autophagy using pharmacological inhibitors, such as 3-methyladenine and bafilomycin A1, or silencing of the autophagy genes ATG12 or BECN1 decreased the Stx2-induced death in Caco-2 cells. Furthermore, there were numerous instances of dilated endoplasmic reticulum (ER) in the Stx2-treated Caco-2 cells, and repression of ER stress due to the depletion of viable candidates of DDIT3 and NUPR1. These processes led to Stx2-induced autophagy and cell death. Finally, the data showed that the pseudokinase TRIB3-mediated DDIT3 expression and AKT1 dephosphorylation upon ER stress were triggered by Stx2. Thus, the data indicate that Stx2 causes autophagic cell death via the ER stress pathway in intestinal epithelial cells.
authors.affiliation: a National Engineering Research Center for Immunobiological Products; Department of Microbiology and Biochemical Pharmacy; College of Pharmacy; Third Military Medical University ; Chongqing , China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Xiu-hua
authors.initials: XH
authors.lastname: Zhao
authors.forename: Hai-guang
authors.initials: HG
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Yao
authors.initials: Y
authors.lastname: Fang
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Yin-ping
authors.initials: YP
authors.lastname: Jia
authors.forename: Pan
authors.initials: P
authors.lastname: Zhu
authors.forename: Jiang
authors.initials: J
authors.lastname: Gu
authors.forename: Jing-xin
authors.initials: JX
authors.lastname: Li
authors.forename: Yong-jun
authors.initials: YJ
authors.lastname: Jiao
authors.forename: Wen-de
authors.initials: WD
authors.lastname: Tong
authors.forename: Marissa
authors.initials: M
authors.lastname: Wang
authors.forename: Quan-ming
authors.initials: QM
authors.lastname: Zou
authors.forename: Feng-cai
authors.initials: FC
authors.lastname: Zhu
authors.forename: Xu-hu
authors.initials: XH
authors.lastname: Mao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D004926:Escherichia coli; D006801:Humans; D008810:Mice, Inbred C57BL; D022603:Shiga Toxins / Q000494:pharmacology*; D051742:Transcription Factor CHOP
chemical_list: D022603:Shiga Toxins; D051742:Transcription Factor CHOP
keywords: 3-MA, 3-methyladenine; AO, acridine orange; ATF4, activating transcription factor 4; ATG, autophagy-related; BECN1, Beclin 1, autophagy-related; Baf A1, bafilomycin A1; CASP3, caspase 3, apoptosis-related cysteine peptidase; DDIT3, DNA-damage-inducible transcript 3; E. coli O157:H7; EHEC O157, Escherichia coli O157:H7; ER stress; FACS, fluorescence activated cell sorting; MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; MAPK, mitogen-activated protein kinase; MDC, monodansylcadaverine; NUPR1, nuclear protein, transcriptional regulator, 1; PARP1, poly (ADP-ribose) polymerase 1; PBS, phosphate-buffered saline; PI, propidium iodide; Shiga toxins; Stxs, Shiga toxins; TEM, transmission electron microscopy; TRIB3, tribbles pseudokinase 3; Thap, thapsigargin; WT, wild type; Z-VAD, Z-VAD-FMK; autophagic cell death; autophagy; Δ, knockout
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