Zinc transport complexes contribute to the homeostatic maintenance of secretory pathway function in vertebrate cells
Zinc transport complexes contribute to the homeostatic maintenance of secretory pathway function in vertebrate cells
复制标题
DOI：
10.1074/jbc.m602470200
复制
发表时间：
2006-06-30
影响因子：
4.8
通讯作者：
Kambe, Taiho
中科院分区：
文献类型：
--
作者：
Ishihara, Kaori;Yamazaki, Tomohiro;Kambe, Taiho
锌转运蛋白在广泛的生化过程中发挥着重要作用。在这里，我们报告了 ZnT5/ZnT6 异源寡聚复合物在分泌途径中的重要功能。与内源性鸡组织非特异性 ALP 活性相比，ZnT5(-)ZnT7(-/-) 细胞中表达的人组织非特异性碱性磷酸酶 (ALP) 活性显着降低。 ZnT5(-)ZnT7(-/-) 细胞中无活性的人体组织非特异性 ALP 通过蛋白酶体介导的降解而被降解，而不被运输到质膜。与在缺锌条件下培养的野生型细胞一样，ZnT5(-)ZnT7(-/-)细胞表现出未折叠蛋白反应的加剧，表明这两种复合物在分泌途径功能的稳态维持中发挥作用。此外，我们发现各种细胞系中 ZnT5 mRNA 的表达因内质网应激而上调。 hZnT5转录本的上调是由转录因子XBP1通过hZnT5启动子中的TGACGTGG序列介导的，该序列在小鼠和鸡的ZnT5基因中高度保守。这些结果表明，锌转运到分泌途径受到严格调节，以维持脊椎动物细胞中分泌途径功能的稳态。
Zinc transporters play important roles in a wide range of biochemical processes. Here we report an important function of ZnT5/ZnT6 hetero-oligomeric complexes in the secretory pathway. The activity of human tissue- nonspecific alkaline phosphatase (ALP) expressed in ZnT5(-)ZnT7(-/-) cells was significantly reduced compared with that expressed in wild-type cells as in the case of endogenous chicken tissue- nonspecific ALP activity. The inactive human tissue- nonspecific ALP in ZnT5(-)ZnT7(-/-) cells was degraded by proteasome-mediated degradation without being trafficked to the plasma membrane. ZnT5(-)ZnT7(-/-) cells showed exacerbation of the unfolded protein response as did the wild-type cells cultured under a zinc-deficient condition, revealing that both complexes play a role in homeostatic maintenance of secretory pathway function. Furthermore, we showed that expression of ZnT5 mRNA was up-regulated by the endoplasmic reticulum stress in various cell lines. The up-regulation of the hZnT5 transcript was mediated by transcription factor XBP1 through the TGACGTGG sequence in the hZnT5 promoter, and this sequence was highly conserved in the ZnT5 genes of mouse and chicken. These results suggest that zinc transport into the secretory pathway is strictly regulated for the homeostatic maintenance of secretory pathway function in vertebrate cells.