Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity

被引:169
作者
Henis-Korenblit, Sivan [1 ]
Zhang, Peichuan [1 ]
Hansen, Malene [1 ]
McCormick, Mark [1 ]
Lee, Seung-Jae [1 ]
Cary, Michael [1 ]
Kenyon, Cynthia [1 ]
机构
[1] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA
基金
美国国家卫生研究院;
关键词
aging; daf-2; insulin signaling; unfolded protein response; UNFOLDED PROTEIN RESPONSE; HEAT-SHOCK FACTOR; C-ELEGANS; CAENORHABDITIS-ELEGANS; DAF-16; DISEASES; PATHWAY;
D O I
10.1073/pnas.1002575107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:9730 / 9735
页数:6
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