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

Henis-Korenblit, Sivan, Zhang, Peichuan, Hansen, Malene, McCormick, Mark, Lee, Seung-Jae, Cary, Michael, Kenyon, Cynthia
Proceedings of the National Academy of Sciences of the United States of America 2010 v.107 no.21 pp. 9730-9735
Caenorhabditis elegans, endoplasmic reticulum, gene expression, genes, homeostasis, longevity, messenger RNA, mutants, proteins, ribonucleases, stress response, stress tolerance, transcription factors, unfolded protein response
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.