A genetic program mediates cold-warming response and promotes stress-induced phenoptosis in C. elegans.
A genetic program mediates cold-warming response and promotes stress-induced phenoptosis in C. elegans.
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作者：
Jiang W;Wei Y;Long Y;Owen A;Wang B;Wu X;Luo S;Dang Y;Ma DK
多细胞生物如何对严重的低温应激作出反应和受到影响在很大程度上是未知的。梭elegans筛选突变体异常响应于冷-暖刺激，我们确定了一个分子遗传途径，包括ISY-1，一个保守的未表征的蛋白质，和ZIP-10，一个bZIP型转录因子。ISY-1通过调节microRNA mir-60来控制ZIP-10的转录程序。在ISY-1和mir-60的下游，zip-10水平在短暂的冷-暖暴露后迅速且特异性地增加。zip-10的长期上调诱导了几个蛋白酶编码基因，并促进了C.优雅zip-10缺陷赋予增强的抵抗长期的冷-暖胁迫，更显着的成年人比幼虫。我们的结论是，ZIP-10的遗传程序介导的冷-暖反应，并可能已演变为促进野生种群的亲缘选择资源有限和热应力条件下。地球上的生命面临着温度的不断变化。大多数像人类这样的温血动物可以保持相当稳定的体温，但冷血动物可以经历体温的剧烈变化。例如，秀丽隐杆线虫的体温可以根据其周围环境而变化很大。这个物种已经进化出一套精致的温度感应机制，甚至可以对细微的波动做出反应，这使得蠕虫能够调整其行为。然而，温度的急剧变化会导致生物体内部发生重大变化。短暂的热暴露可以激活帮助细胞修复受损蛋白质的基因，而冷休克可以影响细胞中蛋白质的产生。虽然C.秀丽线虫可以忍受短期的压力，长期暴露在极端温度下可以杀死蠕虫。到目前为止，还不知道C。秀丽线虫对冷休克作出反应，随后是更温暖的温度，也称为冷-暖。为了解决这个问题，Jiang等人在C. elegans并分离出对冷-暖反应不同的蠕虫。研究结果揭示了一种分子途径，它开启了基因对寒冷变暖的反应。Jiang等人发现，两个基因及其蛋白质ISY-1和ZIP-10控制着其他基因在温度变化时的开启或关闭。当蠕虫长时间暴露在冷-暖环境中时，这一途径仍然活跃，许多蠕虫死亡，特别是老年动物。这些发现表明，这种遗传程序可能已经进化，以帮助年轻的动物在压力条件高和食物资源有限的情况下更好地生存。需要更多的工作来探索这一新的途径及其在冷热休克机制中的意义。受影响的基因在不同的生物体中通常是相同的，因此可以以意想不到的方式进行工程改造，以利于研究和医学应用。例如，心脏病发作或脑损伤的患者暴露在较低的温度下，以防止一旦血流恢复正常，组织损伤的风险。因此，这项研究的结果可能有助于我们了解人体细胞如何对低温做出反应并受到保护。
How multicellular organisms respond to and are impacted by severe hypothermic stress is largely unknown. From C. elegans screens for mutants abnormally responding to cold-warming stimuli, we identify a molecular genetic pathway comprising ISY-1, a conserved uncharacterized protein, and ZIP-10, a bZIP-type transcription factor. ISY-1 gatekeeps the ZIP-10 transcriptional program by regulating the microRNA mir-60. Downstream of ISY-1 and mir-60, zip-10 levels rapidly and specifically increase upon transient cold-warming exposure. Prolonged zip-10 up-regulation induces several protease-encoding genes and promotes stress-induced organismic death, or phenoptosis, of C. elegans. zip-10 deficiency confers enhanced resistance to prolonged cold-warming stress, more prominently in adults than larvae. We conclude that the ZIP-10 genetic program mediates cold-warming response and may have evolved to promote wild-population kin selection under resource-limiting and thermal stress conditions. Life on earth faces constant changes in temperature. Most warm-blooded animals like humans can maintain a fairly stable body temperature, but cold-blooded animals can experience drastic shifts in body temperature. For example, the body temperature of the worm Caenorhabditis elegans can vary greatly depending on its surroundings. This species has evolved an exquisite set of temperature-sensing machineries that can react even to subtle fluctuations, which enables the worm to adjust its behaviour. However, drastic shifts in temperature can cause significant changes within the organism. Transient exposure to heat can activate genes that help cells to repair damaged proteins, while cold shock can influence the production of proteins in the cell. Although C. elegans can tolerate short periods of stress, an extended exposure to extreme temperatures can kill the worm. Until now, it was not known how C. elegans responds to cold shock followed by warmer temperatures, also referred to as cold-warming. To address this question, Jiang et al. created random mutations in C. elegans and isolated the worms that responded to cold-warming differently. The results revealed a molecular pathway that turns on genes in response to cold-warming. Jiang et al. found that two genes and their proteins, ISY-1 and ZIP-10, control which other genes are switched on or off in response to this temperature change. When the worms were exposed to cold-warming over a long period, the pathway remained active and many of the worms died, in particular older animals. These findings suggest that this genetic program might have evolved to help younger animals survive better when stress conditions are high and food resources limited. More work is needed to explore this new pathway and its implication in the heat-cold shock mechanisms. The affected genes are often the same across different organisms and can therefore be engineered to benefit research and medical applications in unexpected ways. For example, patients suffering a heart attack or brain injury are exposed to colder temperature to prevent the risk of tissue injuries once the blood flow goes back to normal. Therefore, the findings of this study may help us to understand how human cells respond to and are protected by low temperature.