Deficiency in intestinal epithelial O‐GlcNAcylation predisposes to gut inflammation

Abstract

Post‐translational modifications in intestinal epithelial cells (IECs) allow for precise control in intestinal homeostasis, the breakdown of which may precipitate the pathological damage and inflammation in inflammatory bowel disease. The O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) modification on intracellular proteins controls diverse biological processes; however, its roles in intestinal homeostasis are still largely unexplored. Here, we found that levels of protein O‐GlcNAcylation and the expression of O‐GlcNAc transferase (OGT), the enzyme adding the O‐GlcNAc moiety, were reduced in IECs in human IBD patients. Deletion of OGT specifically in IECs resulted in disrupted epithelial barrier, microbial dysbiosis, Paneth cell dysfunction, and intestinal inflammation in mice. Using fecal microbiota transplantation in mice, we demonstrated that microbial dysbiosis although was insufficient to induce spontaneous inflammation but exacerbated chemical‐induced colitis. Paneth cell‐specific deletion of OGT led to Paneth cell dysfunction, which might predispose mice to chemical‐induced colitis. On the other hand, the augmentation of O‐GlcNAc signaling by inhibiting O‐GlcNAcase, the enzyme removing O‐GlcNAcylation, alleviated chemical‐induced colitis. Our data reveal that protein O‐GlcNAcylation in IECs controls key regulatory mechanisms to maintain mucosal homeostasis.

O-GlcNAcylation and its role in the immune system

“…In addition, IFN-γ-induced STAT1 activation is required for the induced expression of Th1 lineage-determining transcription factor, T-bet [147]. Previous studies indicated that O-GlcNAcylated STAT1 enhanced the stability of phosphorylated STAT1 and its downstream signaling transduction [148,149]. Whether O-GlcNAcylation of STAT1 participates in the regulation of Th1 differentiation needs to be further determined.…”

Role of nutrient-driven O-GlcNAc-post-translational modification in pancreatic exocrine and endocrine islet development

“…This is further supported by our data showing reduced pancreas weight and β-cell mass in adult OgtKO Panc mice after pancreas development. Hyper-O-GlcNAcylation is a general feature of evading apoptosis in cancer cells (Ferrer et al, 2014), and Ogt loss has been reported to regulate apoptosis in various cell types, including neurons (Wang et al, 2016) and intestinal epithelial cells (Zhao et al, 2018). Ogt deletion in pancreatic β-cells causes diabetes with remarked reduction in β-cell mass associated with increased apoptosis at P90 (Alejandro et al, 2015;Ida et al, 2017).…”

Post-Translational Modifications of Transcription Factors Harnessing the Etiology and Pathophysiology in Colonic Diseases

“…Recent studies reported that levels of protein O-GlcNAcylation and the expression of O-GlcNAc transferase (OGT) were reduced in intestinal epithelial cells (IEC) of patients with UC and CD [108,109]. Similar to phosphorylation, OGT-modulated O-GlcNAcylation of Foxp3 is also critical for the lineage stability and effector function of Treg cells.…”

“…Similar to phosphorylation, OGT-modulated O-GlcNAcylation of Foxp3 is also critical for the lineage stability and effector function of Treg cells. Mice with OGT deficiency either in IEC or Treg cells exhibited severe intestinal inflammation, indicating that OGT-modulated and Foxp3-based O-GlcNAcylation can regulate the development of colitis [108,110]. Pharmacological enhancement of intracellular O-GlcNAc levels promoted the increase in SOCS3 gene expression and the suppressive activity of human Treg cells [110].…”

“…Ser19/Thr175 phosphorylation regulation of Foxp3 transcriptional activity for inhibition of inflammation [96,97] Ser422 phosphorylation inhibition of Foxp3 binding ability for promotion of inflammation [98] Ser418 phosphorylation regulation of Treg population [100,101] Lys31/Lys262/Lys267 acetylation modulation of Treg function for inhibition of inflammation [104] ubiquitination regulation of Foxp3 protein stability for inhibition of inflammation [105][106][107] O-GlcNAcylation regulation of Treg cell lineage stability for inhibition of inflammation [108,110]…”