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

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

The formation of Ca 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 oxi...

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Bibliographic Details
Published in:Science signaling Vol. 14; no. 709; p. eabe3800
Main Authors: Gu, Feng, Krüger, Aileen, Roggenkamp, Hannes G, Alpers, Rick, Lodygin, Dmitri, Jaquet, Vincent, Möckl, Franziska, Hernandez C, Lola C, Winterberg, Kai, Bauche, Andreas, Rosche, Anette, Grasberger, Helmut, Kao, John Y, Schetelig, Daniel, Werner, René, Schröder, Katrin, Carty, Michael, Bowie, Andrew G, Huber, Samuel, Meier, Chris, Mittrücker, Hans-Willi, Heeren, Joerg, Krause, Karl-Heinz, Flügel, Alexander, Diercks, Björn-Philipp, Guse, Andreas H
Format: Journal Article
Language:English
Published: United States 16-11-2021
Subjects:
Animals
Calcium Signaling
Dual Oxidases - genetics
HEK293 Cells
Humans
Jurkat Cells
Lymphocyte Activation
Mice
Mice, Knockout
NADP - analogs & derivatives
NADP - biosynthesis
NADPH Oxidases - genetics
T-Lymphocytes - enzymology
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Summary:The formation of Ca 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 signaling were decreased in mouse T cells with double knockout of and but not with knockout of or Ca microdomains in the first 15 s upon T cell activation were significantly decreased in but not in T cells, whereas both DUOX1 and DUOX2 were required for global Ca 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.
ISSN:1937-9145
DOI:10.1126/scisignal.abe3800