Enhanced O-linked Glcnacylation in Crohn's disease promotes intestinal inflammation
Qian-Hui Sun,
Yi-Shu Wang,
Guolong Liu,
Hong-Lan Zhou,
Yong-Ping Jian,
Ming-Di Liu,
Dan Zhang,
Qiang Ding,
Rui-Xun Zhao,
Jian-Feng Chen,
Yi-Ning Li,
Jiyong Liang,
Yu-Lin Li,
Cheng-Shi Quan,
Zhi-Xiang Xu
Affiliations
Qian-Hui Sun
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Yi-Shu Wang
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
Guolong Liu
Department of Medical Oncology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
Hong-Lan Zhou
Department of Urology, The First Hospital of Jilin University, Changchun, China
Yong-Ping Jian
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
Ming-Di Liu
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
Dan Zhang
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
Qiang Ding
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Rui-Xun Zhao
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Jian-Feng Chen
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Yi-Ning Li
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Jiyong Liang
Department of Neurosurgery, UT MD Anderson Cancer Center, Houston, TX 77030, United States
Yu-Lin Li
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China; Corresponding authors.
Cheng-Shi Quan
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China; Corresponding authors.
Zhi-Xiang Xu
Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China; College of Biological Sciences, Henan University, Kaifeng, China; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Corresponding author at: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
Background: Treatment of Crohn's disease (CD) remains to be a challenge due to limited insights for its pathogenesis. We aimed to determine the role of O-Linked β-N-acetylglucosamine (O-GlcNAc) in the development of CD and evaluate therapeutic effects of O-GlcNAc inhibitors on CD. Methods: O-GlcNAc in intestinal epithelial tissues of CD, adherent-invasive Escherichia coli (AIEC) LF82-infected cells and mice was determined by immunoblot and immunohistochemistry. AIEC LF82 and dextran sulfate sodium were administrated into C57BL/6 mice for estabolishing inflammatory bowel disease model and for therapeutic study. Findings: O-GlcNAc was increased in intestinal epithelial tissues of CD patients and AIEC LF82-infected mice. Infection of AIEC LF82 up-regulated the level of UDP-GlcNAc and increased O-GlcNAc in human colon epithelial HCT116 and HT-29 cells. We identified that IKKβ and NF-κB were O-Glycosylated in AIEC LF82-treated cells. Mutations of IKKβ (S733A) and p65 (T352A) abrogated the O-GlcNAc in IKKβ and NF-κB and inhibited AIEC LF82-induced activation of NF-κB. Application of 6-diazO-5-oxO-L-norleucine, an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAc, inactivated NF-κB in AIEC LF82-infected cells, enhanced the formation of autophagy, promoted the removal of cell-associated AIEC LF82, alleviated intestinal epithelial inflammation, and improved the survival of the colitis mice. Interpretation: Intestinal inflammation in CD is associated with increased O-GlcNAc modification, which is required for NF-κB activation and suppression of autophagy. Targeting O-GlcNAc could be an effective therapy for inflammatory bowel disease. Funding: National Natural Science Foundation of China (Nos. 81573087 and 81772924) and International Cooperation Foundation of Jilin Province (20190701006GH). Keywords: Crohn's disease (CD), inflammatory bowel disease, adherent-invasive Escherichia coli (AIEC) LF82, O-Linked β-N-acetylglucosamine (O-GlcNAc), UDP-N-acetylglucosamine (UDP-GlcNAc), NF-κB
