title: Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway.
abstract: The hexosamine biosynthetic pathway (HBP) is a nutrient-sensing metabolic pathway that produces the activated amino sugar UDP-N-acetylglucosamine, a critical substrate for protein glycosylation. Despite its biological significance, little is known about the regulation of HBP flux during nutrient limitation. Here, we report that amino acid or glucose shortage increase GFAT1 production, the first and rate-limiting enzyme of the HBP. GFAT1 is a transcriptional target of the activating transcription factor 4 (ATF4) induced by the GCN2-eIF2α signalling pathway. The increased production of GFAT1 stimulates HBP flux and results in an increase in O-linked β-N-acetylglucosamine protein modifications. Taken together, these findings demonstrate that ATF4 provides a link between nutritional stress and the HBP for the regulation of the O-GlcNAcylation-dependent cellular signalling.
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Chaveroux
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sarcinelli
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Barbet
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Sofiane
authors.initials: S
authors.lastname: Belfeki
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Barthelaix
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Ferraro-Peyret
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Lebecque
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Toufic
authors.initials: T
authors.lastname: Renno
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bruhat
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, 63122 Saint Genès Champanelle, France.|Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, 63000 Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fafournoux
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.|Université de Lyon, Université Lyon 1, F-69000 Lyon, France.|Centre Léon Bérard, F-69008 Lyon, France.
authors.forename: Serge N
authors.initials: SN
authors.lastname: Manié
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D053898:Biosynthetic Pathways; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D006367:HeLa Cells; D006595:Hexosamines / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D019884:Nitrogenous Group Transferases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
chemical_list: D000596:Amino Acids; D006595:Hexosamines; D051701:Activating Transcription Factor 4; D019884:Nitrogenous Group Transferases; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D000117:Acetylglucosamine