Identification of the maturation factor for dual oxidase - Evolution of an eukaryotic operon equivalent
Identification of the maturation factor for dual oxidase - Evolution of an eukaryotic operon equivalent
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DOI：
10.1074/jbc.c600095200
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发表时间：
2006-07-07
影响因子：
4.8
通讯作者：
Refetoff, Samuel
中科院分区：
文献类型：
--
作者：
Grasberger, Helmut;Refetoff, Samuel
双氧化酶2(DUOX2)是一种NADPH：O-2氧化还原酶黄素蛋白，是甲状腺过氧化氢生成器的组成部分，对顶膜激素的合成至关重要。DUOX2基因突变会导致人类先天性甲状腺功能减退。然而，在转基因细胞的质膜上，没有一个功能性的基于DUOX的NADPH氧化酶被重组。DUOX在异源系统的内质网(ER)中的滞留被认为是由于缺乏酶功能成熟所需的未知成分。通过对大规模平行签名测序组织表达数据库的数据挖掘，我们发现了一个与DUOX2并列并共表达的未知基因，命名为DUOX成熟因子(DUOXA2)。Paralog(DUOXA1)与DUOX1类似。导致古代DUOX和DUOXA基因连锁的基因组重排可以追溯到棘皮分化之前。我们证明了DUOXA2，一种内质网驻留的跨膜蛋白的共表达，允许内质网到高尔基体的转变，成熟，并在异源系统中转移到功能性DUOX2的质膜上。DUOXA基因的鉴定对研究DUOX表达调控的分子机制和先天性甲状腺功能减退症的分子遗传学具有重要意义。
Dual oxidase 2 (DUOX2), an NADPH:O-2 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 endo-plasmatic 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 echino-derms. 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.