Requirement of Zinc Transporter SLC39A7/ZIP7 for Dermal Development to Fine-Tune Endoplasmic Reticulum Function by Regulating Protein Disulfide Isomerase
Requirement of Zinc Transporter SLC39A7/ZIP7 for Dermal Development to Fine-Tune Endoplasmic Reticulum Function by Regulating Protein Disulfide Isomerase
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DOI：
10.1016/j.jid.2017.03.031
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发表时间：
2017-08-01
影响因子：
6.5
通讯作者：
Fukada, Toshiyuki
中科院分区：
文献类型：
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作者：
Bin, Bum-Ho;Bhin, Jinhyuk;Fukada, Toshiyuki
皮肤是锌缺乏的第一个表现。然而，锌稳态影响皮肤发育的分子机制在很大程度上仍然未知。在这里，我们表明，锌调节转运蛋白/铁调节转运蛋白样蛋白7（ZIP 7）定位于内质网在结缔组织发育中起着至关重要的作用。在表达胶原蛋白1的组织中缺乏Slc 39 a7/Zip 7基因的小鼠表现出皮肤发育不良。间充质干细胞中ZIP 7的消融抑制了细胞增殖，从而阻止了适当的真皮形成，表明ZIP 7是真皮发育所需的。我们还发现，缺乏ZIP 7的间充质干细胞在内质网中积累锌，这触发了锌依赖性聚集和蛋白质二硫键异构酶的抑制，导致内质网功能障碍。这些结果表明，ZIP 7是间充质干细胞中内质网功能所必需的，因此，对皮肤发育至关重要。
Skin is the first area that manifests zinc deficiency. However, the molecular mechanisms by which zinc homeostasis affects skin development remain largely unknown. Here, we show that zinc-regulation transporter-/iron-regulation transporter-like protein 7 (ZIP7) localized to the endoplasmic reticulum plays critical roles in connective tissue development. Mice lacking the Slc39a7/Zip7 gene in collagen 1-expressing tissue exhibited dermal dysplasia. Ablation of ZIP7 in mesenchymal stem cells inhibited cell proliferation thereby preventing proper dermis formation, indicating that ZIP7 is required for dermal development. We also found that mesenchymal stem cells lacking ZIP7 accumulated zinc in the endoplasmic reticulum, which triggered zinc-dependent aggregation and inhibition of protein disulfide isomerase, leading to endoplasmic reticulum dysfunction. These results suggest that ZIP7 is necessary for endoplasmic reticulum function in mesenchymal stem cells and, as such, is essential for dermal development.