Regulation and function of Zip4, the acrodermatitis enteropathica gene.
Regulation and function of Zip4, the acrodermatitis enteropathica gene.
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DOI：
10.1042/bst0361242
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发表时间：
2008-12
影响因子：
3.9
通讯作者：
Andrews GK
中科院分区：
文献类型：
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作者：
Andrews GK
SLC39A(溶质载体39A)家族由14个成员组成，它们被认为控制锌的吸收进入细胞质。其中，ZIP4对锌的稳态尤为重要。该基因的突变会导致肠病肢端皮炎，这是一种罕见的隐性致死性人类遗传病。本文对我们对小鼠ZIP4基因的调控和功能的研究进行了简要的综述。小鼠ZIP4在与膳食或母体锌吸收相关的组织中表达水平最高，并且该基因和蛋白质受到多种转录后机制的动态调节，以响应锌的可获得性。当缺锌时，ZIP4在肠上皮细胞和内胚层细胞的顶面积聚，这是因为ZIP4的mRNA稳定性和蛋白质稳定性增加。相反，当补充锌时，信使核糖核酸不稳定，蛋白质被迅速内化和降解。通过靶向缺失ZIP4基因的小鼠，揭示了ZIP4在锌稳态中的关键作用。纯合子ZIP4基因敲除的胚胎在早期形态发生过程中死亡，杂合子后代的表达严重不足，并表现出一系列发育缺陷，包括外脑畸形、眼球缺失和严重的生长迟缓。携带ZIP4基因杂合子的小鼠对缺锌高度敏感，这表明携带该基因杂合子的人类对缺锌也非常敏感。
The SLC39A (solute carrier 39A) [ZIP (Zrt-Irt-like protein)] family consists of 14 members which are thought to control zinc uptake into the cytoplasm. Among these, ZIP4 is known to be particularly important for zinc homoeostasis. Mutations in this gene cause acrodermatitis enteropathica, a rare recessive-lethal human genetic disorder. In the present paper, our studies of the regulation and function of the mouse Zip4 gene are briefly reviewed. Mouse Zip4 is expressed at highest levels in tissues involved in absorption of dietary or maternal zinc, and the gene and protein are dynamically regulated by multiple post-transcriptional mechanisms in response to zinc availability. ZIP4 accumulates at the apical surface of enterocytes and endoderm cells when zinc is deficient, because of increased stability of the mRNA and stabilization of the protein. In contrast, when zinc is replenished, the mRNA is destabilized and the protein is internalized and degraded rapidly. The critical importance of ZIP4 in zinc homoeostasis is revealed in mice with targeted deletions of this gene. Homozygous Zip4-knockout embryos die during early morphogenesis and heterozygous offspring are significantly underrepresented and display an array of developmental defects, including exencephalia, anophthalmia and severe growth retardation. Mice heterozygous for Zip4-knockout are hypersensitive to zinc deficiency, which suggests that humans heterozygous for this gene may also be very sensitive to zinc deficiency.