ZIP8 is a recently identified membrane transporter which facilitates uptake of many substrates including both essential and toxic divalent metals (e.g. zinc, manganese, iron, cadmium) and inorganic selenium. Many ZIP8 regulated downstream signals and pathways remain to be elucidated. In this study, we investigated ZIP8 regulatory roles in downstream targets in ZIP8-gain and loss cells and in ZIP8 overexpressed lungs. Our results show that the overexpression of ZIP8 in mouse fibroblast cells (MEF) induces significant morphological change and re-organization of filament actin (F-actin), along with increased cell proliferation and migration rate. In ZIP8 knockout chronic myelogenous leukemia HAP1 cells, significant clonal morphological change with increased cell–cell adhesion was observed. In the ZIP8 overexpressed lung, F-actin was aberrantly enriched around the tracheal branch. In these ZIP8 gain and loss cell lines and ZIP8 transgenic lungs, we identified two relevant transcription factors, NF-κB and Snail2, whose activation is dependent on the ZIP8 level. They were both significantly upregulated in ZIP8 overexpressed cells and lungs. Expression of NF-κB and Snail2 targets, COL1A2 and E-cadherin, was also correspondingly elevated. Taken together, our results suggest that ZIP8 is a new regulator for cell morphology and cytoskeleton which involves NF-κB and Snail2.

中文翻译：

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ZIP8在调节细胞形态和NF-κB/ Snail2信号传导中的作用†

ZIP8是最近发现的一种膜转运蛋白，可促进多种底物的吸收，包括必需和有毒的二价金属（例如锌，锰，铁，镉）和无机硒。许多ZIP8调控的下游信号和途径仍有待阐明。在这项研究中，我们调查了ZIP8在下游目标中的ZIP8调控作用，这些下游目标包含ZIP8增益和丢失细胞以及ZIP8过表达的肺部。我们的结果表明，ZIP8在小鼠成纤维细胞（MEF）中的过表达诱导了显着的形态变化和细丝肌动蛋白（F-actin）的重组，并增加了细胞增殖和迁移速率。在ZIP8基因敲除的慢性粒细胞性白血病HAP1细胞中，观察到明显的克隆形态变化，细胞间粘附增加。在ZIP8过表达的肺中，F-肌动蛋白在气管分支周围异常富集。在这些ZIP8得失细胞系和ZIP8转基因肺中，我们确定了两个相关的转录因子，NF-κB和Snail2，其激活取决于ZIP8水平。它们在ZIP8过表达的细胞和肺中均显着上调。NF-κB和Snail2靶标COL1A2和E-cadherin的表达也相应升高。综上所述，我们的结果表明ZIP8是涉及NF-κB和Snail2的细胞形态和细胞骨架的新调节剂。