title: Shiga toxins induce autophagy leading to differential signalling pathways in toxin-sensitive and toxin-resistant human cells.
abstract: The bacterial virulence factors Shiga toxins (Stxs) are expressed by Shigella dysenteriae serotype 1 and certain Escherichia coli strains. Stxs are protein synthesis inhibitors and induce apoptosis in many cell types. Stxs induce apoptosis via prolonged endoplasmic reticulum stress signalling to activate both extrinsic and intrinsic pathways in human myeloid cells. Studies have shown that autophagy, a lysosome-dependent catabolic process, may be associated with activation of pro-survival or death processes. It is currently unknown if autophagy contributes to apoptosis or protects cells from Stxs. To study cellular responses to Stxs, we intoxicated toxin-sensitive cells (THP-1 and HK-2 cells), and toxin-resistant cells (primary human monocyte-derived macrophages) and examined toxin intracellular trafficking and autophagosome formation. Stxs translocated to different cell compartments in toxin-resistant versus toxin-sensitive cells. Confocal microscopy revealed autophagosome formation in both toxin-resistant and toxin-sensitive cells. Proteolytic cleavage of Atg5 and Beclin-1 plays pivotal roles in switching non-cytotoxic autophagy to cell death signalling. We detected cleaved forms of Atg5 and Beclin-1 in Stx-treated toxin-sensitive cells, while cleaved caspases, calpains, Atg5 and Beclin-1 were not detected in toxin-resistant primary human monocytes and macrophages. These findings suggest that toxin sensitivity correlates with caspase and calpain activation, leading to Atg5 and Beclin-1 cleavage.
authors: Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, Bryan, TX 77807, USA.
authors: Moo-Seung
authors: MS
authors: Lee
authors: Rama P
authors: RP
authors: Cherla
authors: Matthew H
authors: MH
authors: Jenson
authors: Dinorah
authors: D
authors: Leyva-Illades
authors: Margarita
authors: M
authors: Martinez-Moczygemba
authors: Vernon L
authors: VL
authors: Tesh
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004926:Escherichia coli / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D022621:Shiga Toxin; D022603:Shiga Toxins / Q000633:toxicity*; D012762:Shigella dysenteriae / Q000472:pathogenicity*; D015398:Signal Transduction
chemical_list: C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D022603:Shiga Toxins; D022621:Shiga Toxin; D002154:Calpain; D020169:Caspases