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O-GlcNAcylation
A post-translational modification which depends on glucose availability.
O-GlcNAcylation is a reversible post-translational modification of cytosolic, nuclear and mitochondrial proteins. Like phosphorylations, O-GlcNAcylation can control their activity, their stability or their sub-cellular localization, but it uses a sugar (N-Acetyglucosamine or GlcNAc) rather than a phosphate to modify the serine and threonine residues of proteins. O-GlcNAcylation is closely dependent on the nutritional environment of the cell, and in particular on the availability of glucose. In fact, a fraction of the glucose which enters the cell is directed towards the hexosamine biosynthesis pathway and leads to the production of UDP-GlcNAc, the substrate used by OGT (O-GlcNAc Transferase) to O-GlcNAcylate the proteins. The reverse reaction is catalyzed by OGA (O-GlcNAcase), which removes the GlcNAc group from proteins. O-GlcNAcylation has been implicated in various chronic pathologies such as diabetes, obesity and cancer.
O-GlcNAcylation and Metabolic Diseases
Our previous work has shown that O-GlcNAcylation can participate in the phenomenon of gluco-lipotoxicity at the hepatic and beta-pancreatic cell levels (Kuo et al., 2008; Guinez et al., 2011; Fardini et al., 2014; Filhoulaud et al., 2019) in particular by modifying the activity of transcription factors such as FoxO1 and ChREBP. While excess O-GlcNAcylation can have deleterious effects on certain diabetic complications (Issad et al., 2010), several studies suggest that O-GlcNAcylation also has protective effects on inflammatory processes and various cellular stresses (Baudoin and Issad, 2015). Using animal models with targeted OGT deletions, we are currently studying the role of O-GlcNAcylation in the macrophage and liver cell.
O-GlcNAcylation and cancer
Since glucose metabolism is strongly disturbed in cancers, we were also interested in the role of this modification in different cancer cell models (Kanwal et al., 2013, Groussaud et al., 2017, Jiménez-Castillo et al., 2022).
New tools to study O-GlcNAcylation
Our laboratory was part of the pioneering teams involved in the development of the BRET technique (Bioluminescence Resonance Energy Transfer) for the study of cell signaling. We are currently developing BRET tools to monitor, in real time, in living cells, O-GlcNAcylation in different cellular compartments: plasma membrane, cytosol, nucleus (Groussaud et al. 2017; Al-Mukh et al., 2020 ), and more recently, mitochondria (Pagesy et al., 2021).
O-GlcNAcylation in the macrophage
We have shown, in mouse macrophages and human monocyte-derived macrophages, that LPS stimulation induces a general increase in protein O-GlcNAcylation, suggesting an important role of this modification in TLR4 signaling (Al -Mukh et al., 2020). This increase in O-GlcNAcylation induced by LPS is due to a stimulation of the expression of GFAT2 (limiting enzyme of the hexosamine biosynthetic pathway), via the transcription factor FoxO1.