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    O-GlcNAc-glycosylation: when sugar quenches inflammation in the macrophage

    Team Postic-Issad

    O-GlcNAc-glycosylation: when sugar quenches inflammation in the macrophage

     

    A study led by Tarik Issad, in collaboration with Florence Niedergang (Team “Biology of Phagocytes, Infection and Immunity”) and Georges Bismuth (Team “Signaling of immune cells and retroviral infection”) showed that in the macrophage, LPS (a pro-inflammatory component of gram negative bacterial membrane) induces a general increase in protein O-GlcNAcylation. This increase in O-GlcNAcylation constitutes a negative feedback mechanism that limits inflammatory processes induced by LPS (article to appear in The Journal of Immunology).

     

    O-GlcNAc-glycosylation (O-GlcNAcylation) corresponds to the addition of N-Acetyl-glucosamine (GlcNAc) on serine and threonine residues of cytosolic, nuclear and mitochondrial proteins. Like phosphorylation, this reversible modification controls protein location, activity and stability. This modification is achieved by a single enzyme, O-GlcNAc transferase (OGT), which uses UDP-GlcNAc produced from glucose and glutamine in the hexosamine biosynthetic pathway (HBP). The authors observed, in human and murine macrophages, that LPS stimulates O-GlcNAcylation of proteins by inducing the expression of a gene encoding the rate limiting enzyme of the HBP, glutamine fructose 6-phosphate amido-transferase 2 (GFAT2). Induction of GAFT2 by LPS requires the activity of the transcription factor FoxO1, since it is abolished by pharmacological or genetic inhibition of FoxO1 in human or murine macrophages.

     

    In macrophages from OGT knock out mice, the decrease in O-GlcNAcylation leads to an exacerbation of the effect of LPS on the expression of NOS2 and on the production of pro-inflammatory cytokines. These results indicate that the increase in O-GlcNAcylation induced by LPS may be part of a regulatory loop aimed at limiting the pro-inflammatory response of macrophages.

     

     

     

     

    Figure legend: Activation of macrophages by LPS induces the expression of NOS2 and pro-inflammatory cytokines, but also the expression of GFAT2 via a FoxO1-dependent mechanism. Induction of GFAT2 increases the level of O-GlcNAcylation of proteins, which limits inflammatory processes in the macrophage.

      

    This work could suggest new therapeutic approaches to reduce or resolve the inflammation observed in some pathological situations.

     

    Reference

    Al-Mukh, H., Baudoin, L., Bouaboud, A., Sanchez-Salgado, J-L., Maraqa, N., Khair, M., Pagesy, P., Bismuth, G., Niedergang, F., Issad, T. LPS induces GFAT2 expression to promote O-GlcNAcylation and attenuate inflammation in macrophages. The Journal of Immunology, 2020, 205: 000–000, in press.  

    Pré-print :https://www.biorxiv.org/content/10.1101/2020.03.22.002303v1

     

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