Functional studies of Drosophila zinc transporters reveal the mechanism for zinc excretion in Malpighian tubules.
Functional studies of Drosophila zinc transporters reveal the mechanism for zinc excretion in Malpighian tubules.
复制标题
果蝇锌转运蛋白的功能研究揭示了马氏小管锌排泄的机制。
DOI：
10.1186/s12915-017-0355-9
复制
发表时间：
2017-02-14
期刊：
影响因子：
5.4
通讯作者：
Zhou B
中科院分区：
文献类型：
--
作者：
Yin S;Qin Q;Zhou B
锌是参与许多生理过程的必需金属。先前的工作已经确定了一套锌转运蛋白参与果蝇膳食锌的吸收。然而，锌排泄和重吸收，其他两个重要的过程，以维持锌稳态，没有得到很好的理解。在这项工作中，我们筛选了所有潜在的锌转运蛋白Zip（SLC 39）和ZnT（SLC 30）的成员，他们可能的作用，锌排泄在马氏管，昆虫器官功能类似于哺乳动物的肾脏。Zip 71 B（CG 10006，与hZIP 5最同源），除了先前表征的ZnT 35 C（CG 3994）之外，被鉴定为在锌排泄中是关键的。Zip 71 B/dZip 5的小管特异性敲低减少了锌在小管中的积累，但增加了体内的锌水平，导致在锌过量条件下的存活缺陷。Zip 71 B/dZip 5定位于肾小管基底外侧的质膜上，并且在调节肾小管锌稳态方面功能上上位于顶部定位的ZnT 35 C。我们的研究结果表明，Zip 71 B/dZip 5参与锌从循环输入到肾小管细胞，而ZnT 35 C反过来将肾小管锌排出。值得注意的是，在肾脏中表达的哺乳动物ZIP 5的功能类似于苍蝇中的Zip 71 B/dZip 5，而hZIP 4不能补充Zip 71 B/dZip 5功能的丧失。此外，Zip 71 B/dZip 5表达受锌调节，因此，响应于锌的毒性水平，小管可以增加锌流出能力。我们还表征了dZnT 1（CG 17723）在马氏管锌重吸收中的作用。最后，使用肾小管钙化模型，我们能够表明Zip 71 B/dZip 5或ZnT 35 C的敲低能够减轻结石形成，这与它们在肾小管锌稳态中的作用一致。本研究初步勾勒出了果蝇马氏管锌排泄过程的一个较为完整的图像，为哺乳动物的相关研究提供了参考。本文的在线版本（doi：10.1186/s12915-017-0355-9）包含补充材料，可供授权用户使用。
Zinc is an essential metal involved in many physiological processes. Previous work has identified a set of zinc transporters involved in Drosophila dietary zinc absorption. However, zinc excretion and reabsorption, the other two important processes to maintain zinc homeostasis, are not as well understood. In this work, we screened all the potential zinc transporter Zip (SLC39) and ZnT (SLC30) members for their likely roles in zinc excretion in Malpighian tubules, an insect organ functionally analogous to mammalian kidneys. Zip71B (CG10006, most homologous to hZIP5), in addition to the previously characterized ZnT35C (CG3994), was identified as being critical in zinc excretion. Tubule-specific knockdown of Zip71B/dZip5 reduces zinc accumulation in the tubules, but increases zinc levels in the body, resulting in survival defect under zinc excess conditions. Zip71B/dZip5 is localized to the plasma membrane at the basolateral side of the tubules, and is functionally epistatic to the apically localized ZnT35C in regulating the tubule zinc homeostasis. Our results indicate that Zip71B/dZip5 is involved in zinc import into the tubular cells from the circulation, and ZnT35C in turn effluxes the tubular zinc out. Notably, mammalian ZIP5, which is expressed in the kidney, functions analogously to Zip71B/dZip5 in the fly while hZIP4 cannot complement the loss of Zip71B/dZip5 function. Furthermore, Zip71B/dZip5 expression is regulated by zinc so that, in response to toxic levels of zinc, the tubules can increase zinc efflux capability. We also characterized the role of dZnT1 (CG17723) in zinc reabsorption in Malpighian tubules. Finally, using a tubule calcification model, we were able to show that knockdown of Zip71B/dZip5 or ZnT35C was able to mitigate stone formation, consistent with their roles in tubular zinc homeostasis. Our results start to sketch out a relatively complete picture of the zinc excretion process in Drosophila Malpighian tubules, and may provide a reference for relevant mammalian studies. The online version of this article (doi:10.1186/s12915-017-0355-9) contains supplementary material, which is available to authorized users.