Metallothioneins regulate ATP7A trafficking and control cell viability during copper deficiency and excess

文献类型： 外文期刊

第一作者： Gudekar, Nikita

作者： Gudekar, Nikita;Petris, Michael J.;Gudekar, Nikita;Shanbhag, Vinit;Wang, Yanfang;Weisman, Gary A.;Petris, Michael J.;Shanbhag, Vinit;Weisman, Gary A.;Petris, Michael J.;Wang, Yanfang;Petris, Michael J.;Ralle, Martina;Wang, Yanfang

作者机构：

期刊名称：SCIENTIFIC REPORTS （ 影响因子：4.379； 五年影响因子：5.133 ）

ISSN： 2045-2322

年卷期： 2020 年 10 卷 1 期

页码：

收录情况： SCI

摘要： Copper (Cu) is an essential, yet potentially toxic nutrient, as illustrated by inherited diseases of copper deficiency and excess. Elevated expression of the ATP7A Cu exporter is known to confer copper tolerance, however, the contribution of metal-binding metallothioneins is less clear. In this study, we investigated the relative contributions of ATP7A and the metallothioneins MT-I and MT-II to cell viability under conditions of Cu excess or deficiency. Although the loss of ATP7A increased sensitivity to low Cu concentrations, the absence of MTs did not significantly affect Cu tolerance. However, the absence of all three proteins caused a synthetic lethal phenotype due to extreme Cu sensitivity, indicating that MTs are critical for Cu tolerance only in the absence of ATP7A. A lack of MTs resulted in the trafficking of ATP7A from the trans-Golgi complex in a Cu-dependent manner, suggesting that MTs regulate the delivery of Cu to ATP7A. Under Cu deficiency conditions, the absence of MTs and / or ATP7A enhanced cell proliferation compared to wild type cells, suggesting that these proteins compete with essential Cu-dependent pathways when Cu is scarce. These studies reveal new roles for ATP7A and metallothioneins under both Cu deficiency and excess.

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