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首页> 外文期刊>Molecular and Cellular Biology >Novel Proteolytic Processing of the Ectodomain of the Zinc Transporter ZIP4 (SLC39A4) during Zinc Deficiency Is Inhibited by Acrodermatitis Enteropathica Mutations
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Novel Proteolytic Processing of the Ectodomain of the Zinc Transporter ZIP4 (SLC39A4) during Zinc Deficiency Is Inhibited by Acrodermatitis Enteropathica Mutations

机译：锌缺乏症期间锌缺乏转运蛋白ZIP4（SLC39A4）的胞外域的新蛋白水解处理被肠炎性皮炎变种抑制。

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The zinc transporter ZIP4 (SLC39A4) is mutated in humans with the rare, autosomal recessive genetic disease acrodermatitis enteropathica. In mice, this gene is essential during early embryonic development. ZIP4 is dynamically regulated by multiple posttranscriptional mechanisms, and studies of mouse ZIP4 reported herein reveal that the ectodomain, the extracellular amino-terminal half of the protein, is proteolytically removed during prolonged zinc deficiency while the remaining eight-transmembrane carboxyl-terminal half of the protein is accumulated on the plasma membrane as an abundant form of ZIP4. This novel ZIP4 processing occurs in vivo in the intestine and visceral endoderm, in mouse Hepa cells that express the endogenous Slc39a4 gene and in transfected MDCK and CaCo2 cells, but not HEK293 cells. In transfected MDCK and CaCo2 cells, the ectodomain accumulated and remained associated with membranes when zinc was deficient. ZIP4 cleavage was attenuated by inhibitors of endocytosis, which suggests that the processed protein is recycled back to the plasma membrane and that the ectodomain may be internalized. Ectodomain cleavage is inhibited by acrodermatitis enteropathica mutations near a predicted metalloproteinase cleavage site which is also essential for proper ectodomain cleavage, and overexpression of processed ZIP4 or ZIP4 with ectodomain truncations rendered the mouse Mt1 gene hypersensitive to zinc. These finding suggest that the processing of ZIP4 may represent a significant regulatory mechanism controlling its function.
机译：锌转运蛋白ZIP4（SLC39A4）在人类中发生了罕见的常染色体隐性遗传性疾病小肠炎性皮肤炎。在小鼠中，该基因在早期胚胎发育过程中至关重要。 ZIP4受多种转录后机制动态调节，本文报道的小鼠ZIP4的研究显示，长期缺锌期间，蛋白外域（蛋白质的胞外氨基末端一半）被胞外结构域去除，而剩余的8个跨膜羧基末端一半则被蛋白水解去除。蛋白质以丰富的ZIP4形式积累在质膜上。这种新颖的ZIP4加工过程在体内肠道和内脏内胚层，表达内源性 Slc39a4 基因的小鼠肝细胞中以及在转染的MDCK和CaCo2细胞中发生，但在HEK293细胞中不发生。在转染的MDCK和CaCo2细胞中，当锌缺乏时，胞外域积累并保持与膜相关。 ZIP4裂解被内吞作用抑制剂减弱，这表明加工后的蛋白质被循环回到质膜，而胞外域可能被内化。 Ectodomain的切割受到预期的金属蛋白酶切割位点附近的小肠炎性肠炎的突变的抑制，这对于正确的胞外域切割也是必不可少的，加工过的ZIP4或ZIP4的胞外域截短过表达使小鼠 Mt1 基因对锌高度敏感。这些发现表明，ZIP4的加工可能代表了控制其功能的重要调节机制。

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