OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance

Abstract

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensingO-linked β-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase inO-GlcNAc signaling in macrophages.O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. SuppressingO-GlcNAc signaling byO-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1)O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophageO-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

The Role of O-GlcNAcylation in Immune Cell Activation

“…For example, another study found that depletion of OGT in the human macrophage cell line THP-1 adversely affected M2 polarization, but M1 genes were upregulated ( 31 ). OGT also inhibits the pro-inflammatory activation of macrophages by suppressing the phosphorylation of S6 kinase β-1, suppressing mTORC1 signaling, which prevents pro-inflammatory gene transcription ( 32 ). O-GlcNAcylation is therefore shown to be an essential regulator of macrophage function, affecting both the initial inflammatory response of M1 macrophages and the anti-inflammatory response of M2 macrophages.…”

Construction of circRNA-based ceRNA Network to Reveal the Role of circRNAs in the Progression and Prognosis of Hepatocellular Carcinoma

“…Discoveries indicated that S6K1 inhibitors with bevacizumab (anti-VEGF antibody) had potential to modulate the immune response against HCC and immunotherapy methods for HCC [30,31]. O-GlcNAc transferase (OGT) regulated macrophage in ammation by suppressing S6K1 phosphorylation [32]. In addition, IL-2, IL-4, IFN-γ or TNF-α, in tumor B lymphoid cells, could up-regulate S6K1 signaling to enhance cell viability stimulated by B-cell activating factor of the TNF family (BAFF) [33].…”

New Insights Into the Biology of Protein O-GlcNAcylation: Approaches and Observations

“…Further analyses of liver-specific Ogt knockout mice identified phenotypes including hepatomegaly, fibrosis, inflammation, and necroptosis (Zhang et al, 2019). Ogt floxed mice with LyzM-Cre exhibited metabolic and inflammatory phenotypes compared to Ogt floxed mice without LyzM-Cre (Li et al, 2019;Yang et al, 2020b). Macrophages from these mice exhibit increased proinflammatory responses to bacterial endotoxin LPS (Hasanain Al-Mukh et al, 2020).…”