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J. Biol. Chem., Vol. 280, Issue 34, 30046-30054, August 26, 2005

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Dual Oxidase-2 Has an Intrinsic Ca²⁺-dependent H₂O₂-generating Activity^*

Rabii Ameziane-El-Hassani¶, Stanislas Morand||, Jean-Luc Boucher**, Yves-Michel Frapart**, Daphné Apostolou, Diane Agnandji, Sédami Gnidehou, Renée Ohayon, Marie-Sophie Noël-Hudson, Jacques Francon, Khalid Lalaoui, Alain Virion, and Corinne Dupuy

From the Unité 486 INSERM, Université Paris 11, Faculté de Pharmacie, 5, rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France, ^**UMR CNRS 8601, Université René Descartes, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France, and the Département des Sciences du Vivant, Centre National de l'Energie, des Sciences et des Techniques Nucléaires, 10 000 Rabat, Morocco

Duox2 (and probably Duox1) is a glycoflavoprotein involved in thyroid hormone biosynthesis, as the thyroid H₂O₂ generator functionally associated with Tpo (thyroperoxidase). So far, because of the impairment of maturation and of the targeting process, transfecting DUOX into nonthyroid cell lines has not led to the expression of a functional H₂O₂-generating system at the plasma membrane. For the first time, we investigated the H₂O₂-generating activity in the particulate fractions from DUOX2- and DUOX1-transfected HEK293 and Chinese hamster ovary cells. The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca²⁺-dependent H₂O₂-generating activity. The immature Duox proteins had less activity than pig thyrocyte particulate fractions, and their activity depended on their primary structures. Human Duox2 seemed to be more active than human Duox1 but only half as active as its porcine counterpart. TPO co-transfection produced a slight increase in the enzymatic activity, whereas p22^phox, the 22-kDa subunit of the leukocyte NADPH oxidase, had no effect. In previous studies on the mechanism of H₂O₂ formation, it was shown that mature thyroid NADPH oxidase does not release but H₂O₂. Using a spin-trapping technique combined with electron paramagnetic resonance spectroscopy, we confirmed this result but also demonstrated that the partially glycosylated form of Duox2, located in the endoplasmic reticulum, generates superoxide in a calcium-dependent manner. These results suggest that post-translational modifications during the maturation process of Duox2 could be implicated in the mechanism of H₂O₂ formation by favoring intramolecular superoxide dismutation.

Received for publication, January 14, 2005 , and in revised form, June 20, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Recipient of a fellowship from the Commissariat à l'Energie Atomique (Paris, France).

^|| Recipients of a fellowship from the National Education, Research, and Technology Ministry.

Recipient of a fellowship from the French Embassy in Benin.

To whom correspondence should be addressed. Tel.: 33-46-83-59-60; Fax: 33-46-83-58-71; E-mail: corinne.dupuy{at}cep.u-psud.fr.

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