HIF-1 is required for heat acclimation in the nematode Caenorhabditis elegans
HIF-1 is required for heat acclimation in the nematode Caenorhabditis elegans
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DOI：
10.1152/physiolgenomics.00179.2002
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发表时间：
2003-06-24
影响因子：
4.6
通讯作者：
Horowitz, M
中科院分区：
文献类型：
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作者：
Treinin, M;Shliar, J;Horowitz, M
长期暴露在环境高温下可通过热适应(AC)提高耐受性。我们以前在哺乳动物上的数据表明，对编码应激蛋白和能量代谢酶的基因的表达进行重新编程起着重要作用。关于通向AC的途径的知识是有限的。为了鉴定它们，我们建立了秀丽线虫AC模型，并测试了与适应反应相关的信号通路发生突变的突变体。通过将线虫成虫保持在25℃下18小时，可提高野生线虫在热应激(35℃)下的耐热性，并对缺氧和镉具有保护作用。生存曲线表明，表现为耐热性增强的胰岛素受体途径和功能丧失的daf-16(介导DAF-2信号的转录因子)突变体均受益于AC，表明胰岛素受体途径不介导AC。相比之下，HIF-1功能丧失株没有表现出驯化，未驯化的VHL-1和EGL-9突变体(高表达HIF-1)比野生型具有更强的耐热性。与哺乳动物一样，野生型AC线虫中HIF-1和HSP72的水平增加。在AC HIF-1突变体中也观察到HSP72上调，但不足以提高热/应激耐受性，这表明HIF-1上调是驯化所必需的，而在没有HIF-1的情况下HSP72上调是不够的。我们的结论是，HIF-1上调既是进化上保守的，也是热适应的必要组成部分。HIF-1的已知靶点表明，代谢适应对于AC依赖的热和重金属耐受性至关重要，此外，它们在低氧适应中的已知作用也是必不可少的。
Chronic exposure to environmental heat improves tolerance via heat acclimation (AC). Our previous data on mammals indicate that reprogramming the expression of genes coding for stress proteins and energy-metabolism enzymes plays a major role. Knowledge of pathways leading to AC is limited. For their identification, we established a Caenorhabditis elegans AC model and tested mutants in which signaling pathways pertinent to acclimatory responses are mutated. AC attained by maintaining adult C. elegans at 25 degreesC for 18 h enhanced heat endurance of wild-type worms subjected to heat stress (35 degreesC) and conferred protection against hypoxia and cadmium. Survival curves demonstrated that both daf-2 (insulin receptor pathway) showing enhanced heat tolerance and daf-16 loss-of-function (a transcription factor mediating DAF-2 signaling) mutants benefit from AC, suggesting that the insulin receptor pathway does not mediate AC. In contrast, the hif-1 (hypoxia inducible factor) loss-of-function strain did not show acclimation, and non-acclimated vhl-1 and egl-9 mutants (overexpressing HIF-1) had greater heat endurance than the wild type. Like mammals, HIF-1 and HSP72 levels increased in the wild-type AC nematodes. HSP72 upregulation in AC hif-1 mutants was also observed; however, it was insufficient to improve heat/stress tolerance, suggesting that HIF-1 upregulation is essential for acclimation, whereas HSP72 upregulation in the absence of HIF-1 is inadequate. We conclude that HIF-1 upregulation is both an evolutionarily conserved and a necessary component of heat acclimation. The known targets of HIF-1 imply that metabolic adaptations are essential for AC-dependent tolerance to heat and heavy metals, in addition to their known role in hypoxic adaptation.