Abstract
Shiga toxins (Stxs) expressed by the enterohaemorrhagic Escherichia coli and enteric Shigella dysenteriae 1 pathogens are protein synthesis inhibitors. Stxs have been shown to induce apoptosis via the activation of extrinsic and intrinsic pathways in many cell types (epithelial, endothelial, and B cells) but the link between the protein synthesis inhibition and caspase activation is still unclear. Endoplasmic reticulum (ER) stress induced by the inhibition of protein synthesis may be this missing link. Here, we show that the treatment of Burkitt lymphoma (BL) cells with verotoxin-1 (VT-1 or Stx1) consistently induced the ER stress response by activation of IRE1 and ATF6—two ER stress sensors—followed by increased expression of the transcription factor C/REB homologous protein (CHOP). However, our data suggest that, although ER stress is systematically induced by VT-1 in BL cells, its role in cell death appears to be cell specific and can be the opposite: ER stress may enhance VT-1-induced apoptosis through CHOP or play a protective role through ER-phagy, depending on the cell line. Several engineered Stxs are currently under investigation as potential anti-cancer agents. Our results suggest that a better understanding of the signaling pathways induced by Stxs is needed before using them in the clinic.
Highlights
Shiga toxins (Stxs), known as verotoxins (VTs) or Shiga-like toxins (SLTs), are a family of cytotoxic proteins, structurally and functionally related, that are produced by the enteric pathogensShigella dysenteriae type 1and Stx-producing Escherichia coli (STEC)
We did not observe any increases in activating transcription factor 4 (ATF4) levels, neither in BL2 nor Ramos cells, whereas ATF4 was clearly induced in these cells when they were treated with Thapsigargin, a well-known stress inducer. These results show that the PERK/eIF2α/ATF4 signaling pathway was not activated by VT-1 treatment of Burkitt lymphoma (BL) cells
Our results show that VT-1 induces an Endoplasmic reticulum (ER) stress response in both BL cell lines but only at the transcriptional regulation level and not at the translational level (PERK/eIF2α/ATF4)
Summary
Shiga toxins (Stxs), known as verotoxins (VTs) or Shiga-like toxins (SLTs), are a family of cytotoxic proteins, structurally and functionally related, that are produced by the enteric pathogens. Shigella dysenteriae type 1and Stx-producing Escherichia coli (STEC). Two major types of Stxs have been described, VT-1 (or Stx1) and VT-2 (or Stx2), which display 56% amino-acid identity. A broad spectrum of human diseases is associated with Stx-producing organisms, ranging from mild watery diarrhea to bloody diarrhea, hemorrhagic colitis, and life threatening hemolytic uremic syndrome (HUS). Infection with Stx-producing bacteria continues to be a significant worldwide public health problem. In the absence of a vaccine or effective therapy to treat the disease, prevention and supportive therapies are currently the main tools to fight such contamination [1,2]. An improved understanding of Toxins 2020, 12, 316; doi:10.3390/toxins12050316 www.mdpi.com/journal/toxins
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