title: [Protein O-GlcNAcylation and regulation of cell signalling: involvement in pathophysiology].
abstract: O-GlcNAcylation corresponds to the addition of N-acetyl glucosamine (GlcNAc) on serine or threonine residues of cytosolic and nuclear proteins. This reversible post-translational modification regulates protein phosphorylation, sub-cellular localisation, stability and activity. Only two enzymes, OGT (O-linked N-acetyl-glucosaminyltransferase) and OGA (O-linked N-acetyl-β-D glucosaminidase), control the addition and removal of GlcNAc from more than a thousand of proteins. Alternative splicing generates different isoforms of OGT and OGA, and address these enzymes to different sub-cellular compartments (mitochondria, cytosol...), restraining their action to specific subsets of substrates. Moreover, interaction with adaptor proteins may also help address these enzymes to specific substrates. Alterations in protein O-GlcNAcylation have been observed in a number of important human diseases, such as Alzheimer, cancer and diabetes. A reciprocal relationship between Tau protein phosphorylation and O-GlcNAcylation has been observed, and decreased O-GlcNAcylation in the brain of patients with Alzheimer diseases may favour Tau aggregation, destabilisation of microtubules and neuronal alterations. Alterations in OGT/OGA expression levels, and in protein O-GlcNAcylation, have been described in different types of cancer, and much evidence indicates that O-GlcNAcylation may participate in abnormal proliferation and migration of cancer cells. O-GlcNAcylation of transcription factors and signalling effectors may also participate in defects observed in diabetes. Indeed, in situation of chronic hyperglycaemia, abnormal O-GlcNAcylation may have deleterious effect on insulin secretion and action, resulting in further impairment of glucose homeostasis. Therefore, O-GlcNAcylation appears to be a major regulator of cellular activities and may play an important part in different human diseases. However, because of the large spectrum of OGT and OGA substrates, targeting O-GlcNAc for treatment of these diseases will be a highly challenging task.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France - INSERM, U1016, Paris, France.
authors.forename: Tarik
authors.initials: T
authors.lastname: Issad
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France - INSERM, U1016, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pagesy
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D004194:Disease / Q000209:etiology*; D006596:Hexosaminidases / Q000502:physiology; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D009687:Nuclear Proteins; D011506:Proteins; D017351:N-Acetylglucosaminyltransferases; D006596:Hexosaminidases; D000117:Acetylglucosamine