Inhibition of O-GlcNAcylation protects from Shiga toxin-mediated cell injury and lethality in host

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Title
Inhibition of O-GlcNAcylation protects from Shiga toxin-mediated cell injury and lethality in host
Author(s)
Kyung-Soo Lee; Jieun Lee; Pureum Lee; Bong Chan Jeon; Min Yeong Song; Sojung Kwak; Jungwoon Lee; J S Kim; Doo-Jin Kim; Ji Hyung Kim; V L Tesh; Mooseung LeeSung-Kyun Park
Bibliographic Citation
EMBO Molecular Medicine, vol. 14, pp. e14678-e14678
Publication Year
2022
Abstract
Shiga toxins (Stxs) produced by enterohemorrhagic Escherichia coli (EHEC) are the major virulence factors responsible for hemorrhagic colitis, which can lead to life-threatening systemic complications including acute renal failure (hemolytic uremic syndrome) and neuropathy. Here, we report that O-GlcNAcylation, a type of post-translational modification, was acutely increased upon induction of endoplasmic reticulum (ER) stress in host cells by Stxs. Suppression of the abnormal Stx-mediated increase in O-GlcNAcylation effectively inhibited apoptotic and inflammatory responses in Stx-susceptible cells. The protective effect of O-GlcNAc inhibition for Stx-mediated pathogenic responses was also verified using three-dimensional (3D)-cultured spheroids or organoids mimicking the human kidney. Treatment with an O-GlcNAcylation inhibitor remarkably improved the major disease symptoms and survival rate for mice intraperitoneally injected with a lethal dose of Stx. In conclusion, this study elucidates O-GlcNAcylation-dependent pathogenic mechanisms of Stxs and demonstrates that inhibition of aberrant O-GlcNAcylation is a potential approach to treat Stx-mediated diseases.
Keyword
ApoptosisHemolytic uremic syndromeInflammationO-GlcNAcylationShiga toxin
ISSN
1757-4676
Publisher
Wiley
DOI
http://dx.doi.org/10.15252/emmm.202114678
Type
Article
Appears in Collections:
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
Division of Research on National Challenges > Infectious Disease Research Center > 1. Journal Articles
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