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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

Authors 

Jun Young ParkYu-Jin JeongSung Kyun ParkSung Jin YoonSong ChoiDae Gwin JeongS W ChungB J LeeJ H KimV L TeshMoo-Seung LeeYoung-Jun Park

Publisher 

MDPI

Issue Date 

2017

Citation 

Toxins

Keywords 

ApoptosisHemolytic uremic syndromeRetinal pigment epithelial cellsShiga toxin type 1 and 2Shiga toxin-producing Escherichia coliShiga toxinsSignaling pathways

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

ISSN 

2072-6651

Link 

http://dx.doi.org/10.3390/toxins9100319

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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