The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia
The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia
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DOI：
10.1152/ajplung.00057.2008
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发表时间：
2008-06-01
影响因子：
4.9
通讯作者：
Knoell, Daren L.
中科院分区：
文献类型：
--
作者：
Besecker, Beth;Bao, Shengying;Knoell, Daren L.
锌是一种必需的微量营养素和细胞保护剂，参与宿主对炎症应激的反应。我们测试了锌转运蛋白（维持细胞内锌浓度的关键调节因子）是否在炎症期间的细胞存活中发挥作用，特别是在肺上皮细胞中。最初，通过RT-PCR定量测量了所有已知人类锌转运蛋白的mRNA转录，包括14个输入蛋白（SLC39A(1-14)）和10个输出蛋白（SLC30A(1-10)），这些转运蛋白来自多个人类供体和BEAS-2B细胞培养，在基线和tnf α刺激条件下获得的人肺上皮细胞。虽然许多锌转运蛋白组成性表达，但只有SLC39A8 (Zip8) mRNA被tnf - α强烈诱导。在基线条件下未常规检测到内源性Zip8蛋白。与之形成鲜明对比的是，tnf - α诱导了一种糖基化蛋白的表达，这种蛋白易位到质膜和线粒体。Zip8表达的增加导致细胞内锌含量的增加，并与tnf - α存在下的细胞存活相一致。使用短干扰RNA探针抑制Zip8表达降低细胞锌含量，线粒体功能受损，从而导致细胞活力丧失。这些数据首次描述了人类Zip8的特征，并显著证明Zip8的上调足以保护肺上皮免受tnf - α诱导的细胞毒性。我们得出的结论是，相对于其他Zip蛋白，Zip8是独特的，它在炎症发作时作为必需的锌进口商，从而促进肺内的细胞保护。
Zinc is an essential micronutrient and cytoprotectant involved in the host response to inflammatory stress. We tested whether zinc transporters, the critical regulators that maintain intracellular zinc concentrations, play a role in cell survival, particularly in lung epithelia, during inflammation. Initially, mRNA transcripts were quantitatively measured by RT-PCR for all known human zinc transporters, including 14 importers (SLC39A(1-14)) and 10 exporters (SLC30A(1-10)), in primary human lung epithelia obtained from multiple human donors and BEAS-2B cell cultures under baseline and TNF-alpha-stimulated conditions. While many zinc transporters were constitutively expressed, only SLC39A8 (Zip8) mRNA was strongly induced by TNF-alpha. Endogenous Zip8 protein was not routinely detected under baseline conditions. In sharp contrast, TNF-alpha induced the expression of a glycosylated protein that translocated to the plasma membrane and mitochondria. Increased Zip8 expression resulted in an increase in intracellular zinc content and coincided with cell survival in the presence of TNF-alpha. Inhibition of Zip8 expression using a short interfering RNA probe reduced cellular zinc content and impaired mitochondrial function in response to TNF-alpha, resulting in loss of cell viability. These data are the first to characterize human Zip8 and remarkably demonstrate that upregulation of Zip8 is sufficient to protect lung epithelia against TNF-alpha-induced cytotoxicity. We conclude that Zip8 is unique, relative to other Zip proteins, by functioning as an essential zinc importer at the onset of inflammation, thereby facilitating cytoprotection within the lung.