期刊
EMBO MOLECULAR MEDICINE
卷 14, 期 1, 页码 -出版社
WILEY
DOI: 10.15252/emmm.202114678
关键词
apoptosis; hemolytic uremic syndrome; inflammation; O-GlcNAcylation; Shiga toxin
资金
- National Research Foundation of Korea (NRF) - Korean government (MSIT) [2018R1C1B6005095, 2021M3A9H3016046]
- Ministry of Education [2019R1I1A2A01041221, 2021R1I1A2057945]
- KRIBB Research Initiative Program
- National Research Foundation of Korea [2021M3A9H3016046, 2018R1C1B6005095] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
This study reveals that O-GlcNAcylation is acutely increased upon induction of ER stress by Shiga toxins, and inhibition of this modification effectively suppresses apoptotic and inflammatory responses in susceptible cells. Inhibition of aberrant O-GlcNAcylation improves major disease symptoms and survival rate in mice injected with a lethal dose of Stx, suggesting it as a potential approach to treat Stx-mediated diseases.
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.
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