Zinc sensing by metal-responsive transcription factor 1 (MTF1) controls metallothionein and ZnT1 expression to buffer the sensitivity of the transcriptome response to zinc
Zinc sensing by metal-responsive transcription factor 1 (MTF1) controls metallothionein and ZnT1 expression to buffer the sensitivity of the transcriptome response to zinc
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DOI：
10.1039/c5mt00305a
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发表时间：
2016-01-01
期刊：
影响因子：
3.4
通讯作者：
Ford, D.
中科院分区：
文献类型：
--
作者：
Hardyman, J. E. J.;Tyson, J.;Ford, D.
只有少数基因是已知的锌响应转录因子MTF 1的直接靶点;因此，本研究的目的是获得对MTF-1调节的转录组锌响应组分的更完整的理解。靶向siRNA用于消耗人肠细胞系Caco-2中的MTF 1表达。我们预测，锌的直接MTF 1靶基因的反应将被废除的MTF 1敲低。令人惊讶的是，更多的基因调控锌MFT 1敲低后，大多数基因，响应锌控制和MTF 1耗尽的条件下有一个增强的反应，在后一种条件。其中包括锌外排体ZnT 1和一组金属硫蛋白基因，这表明其他基因对锌的反应通常通过这些蛋白质的增加来缓冲。我们提出，MTF 1领导一个层次的锌传感器，并通过控制的金属硫蛋白和其他关键蛋白参与控制细胞内锌水平（如ZnT 1）的表达筏改变锌缓冲能力和总细胞锌含量。我们通过过表达金属硫蛋白并观察锌抑制的SLC 30 A5（ZnT 5）启动子响应的预测缩减来测试和验证该模型。该模型提供了一个框架的综合理解细胞锌稳态。因为MT可以结合锌以外的金属，所以这个框架与整个细胞的金属稳态有关。
Only a small number of genes are known direct targets of the zinc-responsive transcription factor MTF1; therefore, the aim of this study was to gain a more complete understanding of the MTF-1 regulated zinc-responsive component of the transcriptome. A targeted siRNA was used to deplete MTF1 expression in the human intestinal cell line Caco-2. We predicted that the response to zinc of direct MTF1 target genes would be abrogated by MTF1 knockdown. Surprisingly, a greater number of genes were regulated by zinc following MFT1 knockdown, and most genes that responded to zinc under both control and MTF1-depleted conditions had an augmented response in the latter condition. Exceptions were the zinc effluxer ZnT1 and a suite of metallothionein genes, suggesting that responses of other genes to zinc are usually buffered by increases in these proteins. We propose that MTF1 heads a hierarchy of zinc sensors, and through controlling the expression of a raft of metallothioneins and other key proteins involved in controlling intracellular zinc levels (e.g. ZnT1) alters zinc buffering capacity and total cellular zinc content. We tested and validated this model by overexpressing metallothionein and observing the predicted curtailment in response of the zinc-repressed SLC30A5 (ZnT5) promoter. The model provides the framework for an integrated understanding of cellular zinc homeostasis. Because MTs can bind metals other than zinc, this framework links with overall cellular metal homeostasis.