T cell Activation Is Driven by an ADP-Dependent Glucokinase Linking Enhanced Glycolysis with Mitochondrial Reactive Oxygen Species Generation
Autor: | Karsten Gülow, Paulius Grigaravicius, Thorsten Ruppert, Silvana Opp, Marcin Kamiński, Hermann Josef Gröne, Marian Kamiński, Przemyslaw Grudnik, Peter H. Krammer, Sven W. Sauer |
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Rok vydání: | 2012 |
Předmět: |
Bioenergetics
Ubiquinone T-Lymphocytes Molecular Sequence Data Receptors Antigen T-Cell Down-Regulation Glycerolphosphate Dehydrogenase Oxidative phosphorylation Mitochondrion Biology Endoplasmic Reticulum Lymphocyte Activation General Biochemistry Genetics and Molecular Biology Protein Structure Secondary Jurkat Cells Glucokinase Humans Glycolysis Amino Acid Sequence RNA Small Interfering lcsh:QH301-705.5 NF-kappa B Warburg effect Archaea Cell biology Mitochondria Cytosol Biochemistry lcsh:Biology (General) Anaerobic glycolysis RNA Interference Reactive Oxygen Species Sequence Alignment |
Zdroj: | Cell Reports, Vol 2, Iss 5, Pp 1300-1315 (2012) |
ISSN: | 2211-1247 |
DOI: | 10.1016/j.celrep.2012.10.009 |
Popis: | SummaryMitochondria-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. |
Databáze: | OpenAIRE |
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