Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity
Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity
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DOI：
10.1073/pnas.1002575107
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发表时间：
2010-05-25
影响因子：
11.1
通讯作者：
Kenyon, Cynthia
中科院分区：
文献类型：
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作者：
Henis-Korenblit, Sivan;Zhang, Peichuan;Kenyon, Cynthia
当未折叠的蛋白质在内质网（ER）中积累时，未折叠的蛋白质反应被激活。这种内质网应激反应通过协调减少翻译、降解错误折叠蛋白和增加内质网驻留分子伴侣水平的过程来恢复内质网稳态。核糖核酸酶肌醇需要蛋白-1（IRE-1）是一种介导非常规剪接的核糖核酸内切酶，其靶标XBP-1转录因子是未折叠蛋白反应的关键介导物。在这项研究中，我们表明，在秀丽隐杆线虫胰岛素/IGF-1途径突变体，IRE-1和XBP-1促进寿命延长和增强抵抗ER应激。我们表明，这些效果不是简单地通过增加剪接的xbp-1 mRNA水平和XBP-1正常靶基因的表达来实现的。相反，在胰岛素/IGF-1途径突变体中，XBP-1与在这些突变体中被激活的FOXO转录因子E16合作，以增强ER应激抗性并激活促进长寿的新基因。
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.