Shiga toxins induce apoptosis and ER stress in human retinal pigment epithelial cells = 감염성 시가독소병인자에 의한 망막색소 상피세포의 괴사 및 소포체 스트레스 유도 병리기전

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Title
Shiga toxins induce apoptosis and ER stress in human retinal pigment epithelial cells = 감염성 시가독소병인자에 의한 망막색소 상피세포의 괴사 및 소포체 스트레스 유도 병리기전
Author(s)
Jun Young Park; Yu-Jin Jeong; Sung Kyun ParkSung Jin Yoon; Song Choi; Dae Gwin Jeong; S W Chung; B J Lee; J H Kim; V L Tesh; Moo-Seung LeeYoung-Jun Park
Bibliographic Citation
Toxins, vol. 9, no. 10, pp. e319-e319
Publication Year
2017
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
Keyword
ApoptosisHemolytic uremic syndromeRetinal pigment epithelial cellsShiga toxin type 1 and 2Shiga toxin-producing Escherichia coliShiga toxinsSignaling pathways
ISSN
2072-6651
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/toxins9100319
Type
Article
Appears in Collections:
Division of Research on National Challenges > Infectious Disease Research Center > 1. Journal Articles
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
Division of Biomaterials Research > Bionanotechnology Research Center > 1. Journal Articles
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