title: The UPR reduces glucose metabolism via IRE1 signaling.
abstract: Neurons are highly dependent on glucose. A disturbance in glucose homeostasis therefore poses a severe risk that is counteracted by activation of stress responses to limit damage and restore the energy balance. A major stress response that is activated under conditions of glucose deprivation is the unfolded protein response (UPR) that is aimed to restore proteostasis in the endoplasmic reticulum. The key signaling of the UPR involves the transient activation of a transcriptional program and an overall reduction of protein synthesis. Since the UPR is strategically positioned to sense and integrate metabolic stress signals, it is likely that - apart from its adaptive response to restore proteostasis - it also directly affects metabolic pathways. Here we investigate the direct role of the UPR in glucose homeostasis. O-GlcNAc is a post-translational modification that is highly responsive to glucose fluctuations. We find that UPR activation results in decreased O-GlcNAc modification, in line with reduced glucose metabolism. Our data indicate that UPR activation has no direct impact on the upstream processes in glucose metabolism; glucose transporter expression, glucose uptake and hexokinase activity. In contrast, prolonged UPR activation decreases glycolysis and mitochondrial metabolism. Decreased mitochondrial respiration is not accompanied by apoptosis or a structural change in mitochondria indicating that the reduction in metabolic rate upon UPR activation is a physiological non-apoptotic response. Metabolic decrease is prevented if the IRE1 pathway of the UPR is inhibited. This indicates that activation of IRE1 signaling induces a reduction in glucose metabolism, as part of an adaptive response.
authors.affiliation: Dept. of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: van der Harg
authors.affiliation: Dept. of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: van Heest
authors.affiliation: Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands; Dept. of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Fabian N
authors.initials: FN
authors.lastname: Bangel
authors.affiliation: Dept. of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Patiwael
authors.affiliation: Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands; Dept. of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jan R T
authors.initials: JR
authors.lastname: van Weering
authors.affiliation: Dept. of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Dept. of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands; Dept. of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: w.scheper@vumc.nl.
authors.forename: Wiep
authors.initials: W
authors.lastname: Scheper
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000222:Adaptation, Physiological; D001692:Biological Transport; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D056811:Unfolded Protein Response
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D051246:Glucose Transport Proteins, Facilitative; D006360:Heat-Shock Proteins; D007527:Isoenzymes; C472074:HK1 protein, human; D006593:Hexokinase; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D005947:Glucose; D000117:Acetylglucosamine
keywords: Glucose homeostasis; Glycolysis; IRE1; Mitochondrial respiration; O-GlcNAcylation; Unfolded protein response