Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca 2+ signaling during T cell activation.

Autor: Gu F; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Krüger A; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Roggenkamp HG; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Alpers R; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Lodygin D; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, 37075 Göttingen, Germany., Jaquet V; Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland., Möckl F; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Hernandez C LC; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Winterberg K; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Bauche A; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Rosche A; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Grasberger H; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA., Kao JY; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA., Schetelig D; Department of Computational Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany., Werner R; Department of Computational Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany., Schröder K; Institute of Cardiovascular Physiology, Goethe-Universität, 60590 Frankfurt, Germany., Carty M; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland., Bowie AG; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland., Huber S; Department of Gastroenterology with Sections Infectiology and Tropical Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Meier C; Organic Chemistry, University of Hamburg, 20146 Hamburg, Germany., Mittrücker HW; Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Heeren J; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Krause KH; Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland., Flügel A; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, 37075 Göttingen, Germany., Diercks BP; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Guse AH; Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2021 Nov 16; Vol. 14 (709), pp. eabe3800. Date of Electronic Publication: 2021 Nov 16.
DOI: 10.1126/scisignal.abe3800
Abstrakt: The formation of Ca 2+ microdomains during T cell activation is initiated by the production of nicotinic acid adenine dinucleotide phosphate (NAADP) from its reduced form NAADPH. The reverse reaction—NAADP to NAADPH—is catalyzed by glucose 6-phosphate dehydrogenase (G6PD). Here, we identified NADPH oxidases NOX and DUOX as NAADP-forming enzymes that convert NAADPH to NAADP under physiological conditions in vitro. T cells express NOX1, NOX2, and, to a minor extent, DUOX1 and DUOX2. Local and global Ca 2+ signaling were decreased in mouse T cells with double knockout of Duoxa1 and Duoxa2 but not with knockout of Nox1 or Nox2. Ca 2+ microdomains in the first 15 s upon T cell activation were significantly decreased in Duox2 −/− but not in Duox1 −/− T cells, whereas both DUOX1 and DUOX2 were required for global Ca 2+ signaling between 4 and 12 min after stimulation. Our findings suggest that a DUOX2- and G6PD-catalyzed redox cycle rapidly produces and degrades NAADP through NAADPH as an inactive intermediate.
Databáze: MEDLINE