Grasberger Helmut, Refetoff Samuel
Department of Medicine, University of Chicago, Illinois 60637, USA.
J Biol Chem. 2006 Jul 7;281(27):18269-72. doi: 10.1074/jbc.C600095200. Epub 2006 May 1.
Dual oxidase 2 (DUOX2), an NADPH:O(2) oxidoreductase flavoprotein, is a component of the thyroid H(2)O(2) 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.
双氧化酶2（DUOX2）是一种NADPH：O₂氧化还原酶黄素蛋白，是甲状腺H₂O₂生成器的一个组成部分，对顶膜处的激素合成至关重要。DUOX2突变会导致人类先天性甲状腺功能减退。然而，在转染细胞的质膜上从未重建过基于DUOX的功能性NADPH氧化酶。有人提出，异源系统中DUOX保留在内质网（ER）中是由于缺乏该酶功能成熟所需的一种未知成分。通过对大规模平行签名测序组织表达数据库进行数据挖掘，我们鉴定出一个未表征的基因，名为DUOX成熟因子（DUOXA2），它与DUOX2头对头排列并共同表达。一个旁系同源物（DUOXA1）同样与DUOX1相关联。导致古老的DUOX和DUOXA基因连锁的基因组重排可以追溯到棘皮动物分化之前。我们证明，内质网驻留跨膜蛋白DUOXA2的共表达允许在异源系统中功能性DUOX2从内质网向高尔基体转变、成熟并转运到质膜。DUOXA基因的鉴定对研究控制DUOX表达的分子机制以及先天性甲状腺功能减退的分子遗传学具有重要意义。
