title: T cell activation is driven by an ADP-dependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation.
abstract: Mitochondria-originating reactive oxygen species (ROS) control T cell receptor (TCR)-induced gene expression. Here, we show that TCR-triggered activation of ADP-dependent glucokinase (ADPGK), an alternative, glycolytic enzyme typical for Archaea, mediates generation of the oxidative signal. We also show that ADPGK is localized in the endoplasmic reticulum and suggest that its active site protrudes toward the cytosol. The ADPGK-driven increase in glycolytic metabolism coincides with TCR-induced glucose uptake, downregulation of mitochondrial respiration, and deviation of glycolysis toward mitochondrial glycerol-3-phosphate dehydrogenase(GPD) shuttle; i.e., a metabolic shift to aerobic glycolysis similar to the Warburg effect. The activation of respiratory-chain-associated GPD2 results in hyperreduction of ubiquinone and ROS release from mitochondria. In parallel, mitochondrial bioenergetics and ultrastructure are altered. Downregulation of ADPGK or GPD2 abundance inhibits oxidative signal generation and induction of NF-κB-dependent gene expression, whereas overexpression of ADPGK potentiates them.
authors.affiliation: Division of Immunogenetics (D030), Tumour Immunology Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. m.kaminski@dkfz.de
authors.forename: Marcin M
authors.initials: MM
authors.lastname: Kamiński
authors.forename: Sven W
authors.initials: SW
authors.lastname: Sauer
authors.forename: Marian
authors.initials: M
authors.lastname: Kamiński
authors.forename: Silvana
authors.initials: S
authors.lastname: Opp
authors.forename: Thorsten
authors.initials: T
authors.lastname: Ruppert
authors.forename: Paulius
authors.initials: P
authors.lastname: Grigaravičius
authors.forename: Przemysław
authors.initials: P
authors.lastname: Grudnik
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Karsten
authors.initials: K
authors.lastname: Gülow
mesh_terms: D000595:Amino Acid Sequence; D001105:Archaea / Q000201:enzymology; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005993:Glycerolphosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D017433:Protein Structure, Secondary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D014451:Ubiquinone; D005993:Glycerolphosphate Dehydrogenase; C420842:ADP-dependent glucokinase; D005941:Glucokinase