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Inhibition of O‐GlcNAcylation protects from Shiga toxin‐mediated cell injury and lethality in host
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Inhibition of O‐GlcNAcylation protects from Shiga toxin‐mediated cell injury and lethality in host
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Journal Article
Inhibition of O‐GlcNAcylation protects from Shiga toxin‐mediated cell injury and lethality in host
2022
Overview
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.
Synopsis
Here we identify a previously unknown link between the O‐GlcNAcylation pathway and the pathogenesis of enterohemorrhagic
E
.
coli
Shiga toxin‐mediated diseases. Given the capacity of these bacterial toxins to subvert normal cellular regulation in the host, this study demonstrates that Shiga toxins alter O‐GlcNAcylation, a type of post‐translational modification, to exacerbate dysfunction in host cell signaling.
Shiga toxins induce acute elevations of O‐GlcNAcylation levels which exacerbate host cell damage
in vitro
and lethality in mice.
Shiga toxin‐induced O‐GlcNAcylation increases apoptosis and inflammation through Akt and p‐65, respectively, in toxin‐susceptible cells and human kidney spheroid or organoid surrogate renal model systems.
Inhibition of elevated O‐GlcNAcylation levels may represent a therapeutic target to ameliorate Shiga toxin‐mediated pathogenesis.
Graphical Abstract
Here we identify a previously unknown link between the O‐GlcNAcylation pathway and the pathogenesis of enterohemorrhagic
E
.
coli
Shiga toxin‐mediated diseases. Given the capacity of these bacterial toxins to subvert normal cellular regulation in the host, this study demonstrates that Shiga toxins alter O‐GlcNAcylation, a type of post‐translational modification, to exacerbate dysfunction in host cell signaling.
