A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity.
A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity.
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DOI：
10.1111/acel.12321
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发表时间：
2015-08
期刊：
影响因子：
7.8
通讯作者：
Veal EA
中科院分区：
文献类型：
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作者：
Oláhová M;Veal EA
过氧化物氧化素（Prx）是一种丰富的巯基过氧化物酶，具有保守的抗衰老作用。与大多数动物不同的是，秀丽隐杆线虫（Caenorhabditis elegans）只编码一种胞质2-Cys Prx (PRDX-2)，这使得它成为研究过氧化物还毒素如何影响动物生理和衰老的绝佳模型。我们之前的研究表明，尽管PRDX-2可以抵抗过氧化物的毒性，但令人费解的是，PRDX-2突变的动物对其他形式的氧化应激具有超强的抵抗力。在这里，我们调查了这种抗性增加的基础。哺乳动物FOXO和Nrf2转录因子直接促进一系列解毒酶的表达。我们发现FOXO同源基因DAF-16和Nrf2同源基因SKN-1是prdx-2突变体蠕虫增强抗逆性所必需的。我们的数据表明，PRDX-2是正常水平胰岛素分泌所必需的，因此在营养丰富的条件下，胰岛素/ igf -1样信号（IIS）抑制DAF-16和SKN-1。有趣的是，PRDX-2的缺失会增加DAF-16和SKN-1的活性，从而增加对亚砷酸盐的抗性，而不会启动其他受is抑制的过程。综上所述，这些数据表明，过氧还蛋白功能的丧失可能通过减少胰岛素分泌来增加应激抵抗，但胰岛素信号的进一步变化需要发育和脂肪代谢的重编程。此外，我们发现PRDX-2的温度依赖延长寿命功能是与几个途径相关的延长寿命所必需的，包括IIS的进一步减少。
Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS-inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature-dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS.