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Toxins 2017, 9(10), 319; doi:10.3390/toxins9100319

Shiga Toxins Induce Apoptosis and ER Stress in Human Retinal Pigment Epithelial Cells

1
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Daejeon 34141, South Korea
2
Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Daejeon 34141, South Korea
3
Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77807, USA
4
Department of Biochemistry, College of Medicine, Konyang University, 158 Gwanjeo-ro, Daejeon 35365, South Korea
5
Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 127 Gajeong-ro, Yuseong-gu, Daejeon 34113, South Korea
6
School of Biological Sciences, College of Natural Sciences, University of Ulsan, 93 Daehak-ro, Ulsan 44610, South Korea
7
Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, South Korea
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editors: Daniel Gillet and Julien Barbier
Received: 29 May 2017 / Revised: 6 October 2017 / Accepted: 6 October 2017 / Published: 13 October 2017
(This article belongs to the Special Issue Ribosome Inactivating Toxins)
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Abstract

Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are the most potent known virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications such as acute renal failure, blindness and neurological abnormalities. Although numerous studies have defined apoptotic responses to Shiga toxin type 1 (Stx1) or Shiga toxin type 2 (Stx2) in a variety of cell types, the potential significance of Stx-induced apoptosis of photoreceptor and pigmented cells of the eye following intoxication is unknown. We explored the use of immortalized human retinal pigment epithelial (RPE) cells as an in vitro model of Stx-induced retinal damage. To the best of our knowledge, this study is the first report that intoxication of RPE cells with Stxs activates both apoptotic cell death signaling and the endoplasmic reticulum (ER) stress response. Using live-cell imaging analysis, fluorescently labeled Stx1 or Stx2 were internalized and routed to the RPE cell endoplasmic reticulum. RPE cells were significantly sensitive to wild type Stxs by 72 h, while the cells survived challenge with enzymatically deficient mutant toxins (Stx1A or Stx2A). Upon exposure to purified Stxs, RPE cells showed activation of a caspase-dependent apoptotic program involving a reduction of mitochondrial transmembrane potential (Δψm), increased activation of ER stress sensors IRE1, PERK and ATF6, and overexpression CHOP and DR5. Finally, we demonstrated that treatment of RPE cells with Stxs resulted in the activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), suggesting that the ribotoxic stress response may be triggered. Collectively, these data support the involvement of Stx-induced apoptosis in ocular complications of intoxication. The evaluation of apoptotic responses to Stxs by cells isolated from multiple organs may reveal unique functional patterns of the cytotoxic actions of these toxins in the systemic complications that follow ingestion of toxin-producing bacteria. View Full-Text
Keywords: Shiga toxins; Shiga toxin type 1 and 2; Shiga toxin-producing Escherichia coli; hemolytic uremic syndrome; signaling pathways; apoptosis; retinal pigment epithelial cells Shiga toxins; Shiga toxin type 1 and 2; Shiga toxin-producing Escherichia coli; hemolytic uremic syndrome; signaling pathways; apoptosis; retinal pigment epithelial cells
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MDPI and ACS Style

Park, J.-Y.; Jeong, Y.-J.; Park, S.-K.; Yoon, S.-J.; Choi, S.; Jeong, D.G.; Chung, S.W.; Lee, B.J.; Kim, J.H.; Tesh, V.L.; Lee, M.-S.; Park, Y.-J. Shiga Toxins Induce Apoptosis and ER Stress in Human Retinal Pigment Epithelial Cells. Toxins 2017, 9, 319.

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