Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation.

Autor:	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
Předmět:	T cells T cell receptors OXIDASES INTRACELLULAR calcium NIACIN NICOTINAMIDE adenine dinucleotide phosphate OXYGEN carriers
Zdroj:	Science Signaling; 11/16/2021, Vol. 14 Issue 709, p1-15, 15p
Abstrakt:	An origin story for NAADP in T cells: Early steps in T cell activation are mediated by the synthesis of Ca²⁺-mobilizing second messenger NAADP, which is produced through oxidation of NAADPH by a previously unknown enzyme. Gu et al. identified NAADPH-oxidizing enzymes that were critical for the early phases of T cell activation. Stimulation of T cell receptors initially results in rapid production of NAADP that induces the formation of localized Ca²⁺ microdomains that eventually lead to more global and sustained intracellular Ca²⁺ signaling. In cultured rat T cells, knockout of DUOX2 reduced local Ca²⁺ microdomain formation, whereas functional knockout of both DUOX1 and DUOX2 in murine T cells suppressed global intracellular Ca²⁺ signaling. The findings identify a critical pair of enzymes in T cell activation. The formation of Ca²⁺ 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 Ca²⁺ signaling were decreased in mouse T cells with double knockout of Duoxa1 and Duoxa2 but not with knockout of Nox1 or Nox2. Ca²⁺ 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 Ca²⁺ 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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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