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J. Biol. Chem., Vol. 281, Issue 27, 18269-18272, July 7, 2006

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Identification of the Maturation Factor for Dual Oxidase

EVOLUTION OF AN EUKARYOTIC OPERON EQUIVALENT^*

Helmut Grasberger¹ and Samuel Refetoff^¶

From the Departments of Medicine, Pediatrics, and ^¶Committee on Genetics, University of Chicago, Chicago, Illinois 60637

Dual oxidase 2 (DUOX2), an NADPH:O₂ oxidoreductase flavoprotein, is a component of the thyroid H₂O₂ generator crucial for hormone synthesis at the apical membrane. Mutations in DUOX2 produce congenital hypothyroidism in humans. However, no functional DUOX-based NADPH oxidase has ever been reconstituted at the plasma membrane of transfected cells. It has been proposed that DUOX retention in the endoplasmatic reticulum (ER) of heterologous systems is due to the lack of an unidentified component required for functional maturation of the enzyme. By data mining of a massively parallel signature sequencing tissue expression data base, we identified an uncharacterized gene named DUOX maturation factor (DUOXA2) arranged head-to-head to and co-expressed with DUOX2. A paralog (DUOXA1) was similarly linked to DUOX1. The genomic rearrangement leading to linkage of ancient DUOX and DUOXA genes could be traced back before the divergence of echinoderms. We demonstrate that co-expression of DUOXA2, an ER-resident transmembrane protein, allows ER-to-Golgi transition, maturation, and translocation to the plasma membrane of functional DUOX2 in a heterologous system. The identification of DUOXA genes has important implications for studies of the molecular mechanisms controlling DUOX expression and the molecular genetics of congenital hypothyroidism.

Received for publication, April 24, 2006

^* This work was supported in part by National Institutes of Health Grants DK15070 and DK20595. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S–3S and Table 4S.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ489734 and DQ489735.

¹ To whom correspondence should be addressed: Dept. of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC3090, Chicago, IL 60637. Tel.: 773-702-9273; Fax: 773-702-6940; E-mail: hgrasber{at}uchicago.edu.

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