Kyung-Soo Lee1,2, Jieun Lee1, Pureum Lee1,2, Bong Chan Jeon2,3, Min Yeong Song1,2, Sojung Kwak1, Jungwoon Lee1,2, Jun-Seob Kim4, Doo-Jin Kim5, Ji Hyung Kim5, Vernon L Tesh6, Moo-Seung Lee1,2,* & Sung-Kyun Park5,*
1Environmental Diseases Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Korea 2Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Korea 3Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Korea 4Department of Nano-Bioenginee ring, Incheon National University, Incheon, Korea 5Infectious Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Korea 6Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, USA
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.