Transition metals activate TFEB in overexpressing cells.
Transition metals activate TFEB in overexpressing cells.
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DOI：
10.1042/bj20140645
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发表时间：
2015-08-15
期刊：
影响因子：
--
通讯作者：
Kiselyov K
中科院分区：
文献类型：
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作者：
Peña KA;Kiselyov K
细胞暴露于微摩尔铜激活重组转录因子EB（TFEB），导致溶酶体网络基因的表达。而TFEB过表达在中度Cu暴露下具有细胞保护作用，它增强了由高水平Cu引起的氧化应激和线粒体损伤。过渡金属毒性是许多人类疾病（包括神经退行性疾病）发病机制中的重要因素。溶酶体已经成为过渡金属毒性的重要因素，因为它们通过内吞、自噬、从细胞质吸收和胞吐来处理过渡金属。转录因子EB（TFEB）调节溶酶体生物发生和响应于溶酶体和/或代谢应激的溶酶体蛋白质的表达。由于过渡金属引起溶酶体功能障碍，我们提出TFEB可能被激活，以驱动基因表达响应过渡金属暴露，这种激活可能会影响过渡金属毒性。我们发现，过渡金属铜（Cu）和铁（Fe）激活重组TFEB和刺激TFEB依赖的基因在TFEB过表达细胞的表达。在表现出强烈的溶酶体胞吐作用的细胞中，TFEB在中等水平的Cu暴露下具有细胞保护作用，降低氧化应激，如通过血红素加氧酶-1（HMOX 1）基因的表达所报道的。然而，在高水平的铜暴露，特别是在细胞与低水平的溶酶体胞吐，激活过表达的TFEB是有毒的，增加氧化应激和线粒体损伤。基于这些数据，我们得出结论，TFEB驱动的基因网络是细胞对过渡金属反应的一个组成部分。这些数据表明TFEB过表达作为治疗方法的局限性和缺点。
Exposure of cells to micromolar Cu activates recombinant transcription factor EB (TFEB), leading to expression of the lysosomal network genes. Whereas TFEB overexpression has a cytoprotective effect under moderate Cu exposure, it enhances oxidative stress and mitochondrial damage caused by high levels of Cu. Transition metal toxicity is an important factor in the pathogenesis of numerous human disorders, including neurodegenerative diseases. Lysosomes have emerged as important factors in transition metal toxicity because they handle transition metals via endocytosis, autophagy, absorption from the cytoplasm and exocytosis. Transcription factor EB (TFEB) regulates lysosomal biogenesis and the expression of lysosomal proteins in response to lysosomal and/or metabolic stresses. Since transition metals cause lysosomal dysfunction, we proposed that TFEB may be activated to drive gene expression in response to transition metal exposure and that such activation may influence transition metal toxicity. We found that transition metals copper (Cu) and iron (Fe) activate recombinant TFEB and stimulate the expression of TFEB-dependent genes in TFEB-overexpressing cells. In cells that show robust lysosomal exocytosis, TFEB was cytoprotective at moderate levels of Cu exposure, decreasing oxidative stress as reported by the expression of heme oxygenase-1 (HMOX1) gene. However, at high levels of Cu exposure, particularly in cells with low levels of lysosomal exocytosis, activation of overexpressed TFEB was toxic, increasing oxidative stress and mitochondrial damage. Based on these data, we conclude that TFEB-driven gene network is a component of the cellular response to transition metals. These data suggest limitations and disadvantages of TFEB overexpression as a therapeutic approach.