The zinc transporter ZIPT-7.1 regulates sperm activation in nematodes.
The zinc transporter ZIPT-7.1 regulates sperm activation in nematodes.
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DOI：
10.1371/journal.pbio.2005069
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发表时间：
2018-06
期刊：
影响因子：
9.8
通讯作者：
Kornfeld K
中科院分区：
文献类型：
--
作者：
Zhao Y;Tan CH;Krauchunas A;Scharf A;Dietrich N;Warnhoff K;Yuan Z;Druzhinina M;Gu SG;Miao L;Singson A;Ellis RE;Kornfeld K
精子激活是细胞分化的一个有趣的例子，在这个过程中，不动的精子细胞经历了一个快速而戏剧性的转变，成为成熟的，能动的精子。因为精子核在转录上是沉默的，所以这种转变不涉及转录变化。虽然秀丽隐杆线虫是研究精子激活的主要模型，但信号通路诱导这种转化的机制仍然很差。在这里，我们表明，一个保守的跨膜锌转运蛋白，ZIPT-7.1，调节小杆线虫精子激活的诱导。zipt-7.1突变的雌雄同体不能自花受精，雄性繁殖能力差，因为突变的精子细胞对激活信号的反应有缺陷。zipt-7.1基因在生殖细胞系中表达，在生殖细胞中起促进精子活化的作用。当在哺乳动物细胞中表达时，ZIPT-7.1以高特异性介导锌转运，并且主要位于内膜上。最后，遗传上位性将zipt-7.1置于spe-8精子激活途径的末端，ZIPT-7.1结合SPE-4，一种调节精子激活的早老素。基于这些结果，我们提出了一个新的精子激活模型。在精子细胞中，无活性的ZIPT-7.1定位于膜性细胞器，其含有比细胞质更高水平的锌。当精子激活被触发时，ZIPT-7.1活性增加，从内部储存中释放锌。由此产生的细胞质锌的增加促进了活化特征的表型变化。因此，锌信号是介导精子激活的信号转导过程中的关键步骤，我们已经确定了锌转运蛋白，这是这个激活过程的核心。精子是具有转录沉默DNA的特化细胞，其已被包装以递送到卵子中。在发育的最后一步，未成熟的精子经历从非运动细胞到能够受精的成熟运动精子的快速转变。触发这种变化的信号并不清楚。通过鉴定线虫中精子激活缺陷的突变体，我们发现了一种保守的跨膜蛋白ZIPT-7.1，它可以转运锌并促进两性精子的激活。ZIPT-7.1在生殖细胞系中表达，并在那里起控制精子活化的作用。当在哺乳动物细胞中异位表达时，该蛋白特异性地跨膜转运锌，并且主要定位于细胞内的膜。以前的遗传学研究已经确定了两条途径介导精子激活C。我们的研究结果表明，zipt-7.1作用于这两种途径之一的末端，即spe-8途径。我们认为，当这一途径触发精子激活时，它通过ZIPT-7.1起作用，ZIPT-7.1介导未成熟精子内部储存的锌的释放。这种释放的锌作为第二信使发挥作用，促进成熟的、能动的精子的分化。
Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a leading model for studies of sperm activation, the mechanisms by which signaling pathways induce this transformation remain poorly characterized. Here we show that a conserved transmembrane zinc transporter, ZIPT-7.1, regulates the induction of sperm activation in Caenorhabditis nematodes. The zipt-7.1 mutant hermaphrodites cannot self-fertilize, and males reproduce poorly, because mutant spermatids are defective in responding to activating signals. The zipt-7.1 gene is expressed in the germ line and functions in germ cells to promote sperm activation. When expressed in mammalian cells, ZIPT-7.1 mediates zinc transport with high specificity and is predominantly located on internal membranes. Finally, genetic epistasis places zipt-7.1 at the end of the spe-8 sperm activation pathway, and ZIPT-7.1 binds SPE-4, a presenilin that regulates sperm activation. Based on these results, we propose a new model for sperm activation. In spermatids, inactive ZIPT-7.1 is localized to the membranous organelles, which contain higher levels of zinc than the cytoplasm. When sperm activation is triggered, ZIPT-7.1 activity increases, releasing zinc from internal stores. The resulting increase in cytoplasmic zinc promotes the phenotypic changes characteristic of activation. Thus, zinc signaling is a key step in the signal transduction process that mediates sperm activation, and we have identified a zinc transporter that is central to this activation process. Sperm are specialized cells with transcriptionally silent DNA that has been packaged for delivery into the egg. In their final step of development, immature sperm undergo a rapid transition from nonmotile cells to mature, motile sperm capable of fertilization. The signals that trigger this change are not clearly understood. By identifying mutants in the roundworm Caenorhabditis elegans that are defective in sperm activation, we discovered a conserved transmembrane protein, ZIPT-7.1, that transports zinc and promotes sperm activation in both sexes. ZIPT-7.1 is expressed in the germ line and functions there to control sperm activation. When expressed ectopically in mammalian cells, the protein specifically transports zinc across membranes and localizes primarily to membranes within the cell. Previous genetic studies had identified two pathways that mediate sperm activation in C. elegans, and our results suggest that zipt-7.1 acts at the end of one of these two, the spe-8 pathway. We propose that when this pathway triggers sperm activation, it acts through ZIPT-7.1, which mediates the release of zinc from internal stores in the immature sperm. This released zinc functions as a second messenger to promote the differentiation of mature, motile sperm.
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