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Accueil > Research > Research teams > O-GlcNAcylation, cell signaling and cell cycle > Presentation

O-GlcNAcylation, cell signaling and cell cycle

Presentation

Our team focuses its themes of research on the biological functions of O-GlcNAcylation, a dynamic glycosylation such as phosphorylation with which it works in concert or, at the opposite, it competes. O-GlcNAcylation is confined in the cytosolic, nuclear and mitochondrial compartments. The transfer and the removal of the GlcNAc residue is controlled by OGT (O-GlcNAc transferase), that uses the nutritional sensor UDP-GlcNAc as the sugar donor, and OGA (O-GlcNAcase) respectively. UDP-GlcNAc levels, supplied by the hexosamine biosynthetic pathway (HBP), closely correlate with nutritional status of the cell since several metabolic pathways converge on its biosynthesis. Thus, because of its strategically metabolic position, it is suggested that O-GlcNAcylation regulates the fundamental cellular functions in a nutrition-dependent manner. Our team follows 4 research axes (i-iv) focused around the study of this glycosylation. (i) The activity of OGT is essential for the activation of the PI3K and MAPK pathways. To adapt to the environmental changes the cell modify its metabolism par the way of signaling pathways spatiotemporally regulated by post-translational (accordingly, we have recently undertaken the regulation of the mTOR pathway by O-GlcNAcylation). We demonstrated that OGT’s catalytic activity is necessary for the activation of the MAPK and PI3K pathways and in return synthesis of OGT is controlled by PI3K. Therefore, a regulatory "crosstalk" between the PI3K pathway and OGT activation exists. (ii) O-GlcNAcylation is a regulator of the cell cycle. OGT silencing decreased the expression of cyclins B1 and D1. Growth factors induce the expression of OGT that in return promotes expression of cyclin D1 that drives the progression of cyclin D1 along the G1 phase of the cell cycle. During the G1/S transition, we observed a global decrease of the O-GlcNAcylated proteins level that correlated with an increase in OGA activity. We identified more than fifty proteins which O-GlcNAc content varied during G1/S among which MCM (MiniChromosome Maintenance) indispensable for the pre-replication complex and that partly focus our attention. (iii) Impact of O-GlcNAcylated beta-catenin on colorectal cancer emergence. We observed that O-GlcNAcylation of beta-catenin interferes with its expression and its transcriptional capabilities. This part of our activities is led in a context of colorectal cancer (CRC) (team affiliated to the SIRIC ONCOLille), a leading cause of mortality and morbidity by cancer. Overfeeding contributes to the emergence of CRCs and, more generally, these cancers are linked to metabolic diseases, e.g. diabetes and obesity. Since O-GlcNAcylation is linked to the production of UDP-GlcNAc, the final product of HBP supplied by most of the metabolisms, we seek a relationship between feeding, glycosylation, aberrant stability of beta-catenin and CRC. These results suggest that uncontrolled O-GlcNAcylation of beta-catenin is in part responsible for the impact of nutritional disorders on the emergence of CRC. (iv) Regulation of FAS by O-GlcNAcylation. FAS (Fatty acid synthase) is an enzyme crucial for energy storage and for cell division. Lastly, we found that FAS is regulated by O-GlcNAcylation, at the expression and catalytic activity levels, and that it is a partner of interaction of OGT. We propose that expression of FAS, just like beta-catenin, is O-GlcNAc-dependant what should allow to join cell proliferation and activity of the enzyme in a nutritional context.

O-GlcNAcylation is confined within the cytoplasmic, nuclear and mitochondrial compartments
O-GlcNAcylation is confined within the cytoplasmic, nuclear and mitochondrial compartments
In contrast with complex glycosylations that occur in endoplasmic reticulum, Golgi apparatus and more largely along the secretory pathway, O-GlcNAcylated proteins are mainly located in the cytosol and nucleus. It has also been evidenced that O-GlcNAcylation occurs in mitochondria (an isoform of OGT, mOGT, has been described in mitochondria) and at the cytoplasmic face of the plasma membrane, in the close vicinity to lipid rafts (from Vercoutter-Edouart et al., 2015).