Inhibition of O-GlcNAcylation protects from Shiga toxin-mediated cell injury and lethality in host.
Kyung-Soo LeeJieun LeePureum LeeBong Chan JeonMin Yeong SongSojung KwakJungwoon LeeJun-Seob KimDoo-Jin KimJi Hyung KimVernon L TeshMoo-Seung LeeSung-Kyun ParkPublished in: EMBO molecular medicine (2021)
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.
Keyphrases
- escherichia coli
- induced apoptosis
- endoplasmic reticulum
- cell cycle arrest
- cell death
- stem cells
- physical activity
- type diabetes
- oxidative stress
- signaling pathway
- insulin resistance
- case report
- risk assessment
- metabolic syndrome
- anti inflammatory
- mesenchymal stem cells
- cell proliferation
- multidrug resistant
- pi k akt
- extracorporeal membrane oxygenation
- free survival