Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 107 (21): 9730-9735

Copyright © 2010 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / GENETICS

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

Sivan Henis-Korenblit1, Peichuan Zhang, Malene Hansen2, Mark McCormick, Seung-Jae Lee3, Michael Cary, and Cynthia Kenyon4

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158

Contributed by Cynthia Kenyon, March 11, 2010 (sent for review December 2, 2009)

Abstract: 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.

Key Words: aging • daf-2 • insulin signaling • unfolded protein response


Author contributions: S.H.-K. and C.K. designed research; S.H.-K., P.Z., M.H., M.M., and S.-J.L. performed research; S.H.-K., M.C., and C.K. analyzed data; and S.H.-K. and C.K. wrote the paper.

1Present address: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.

2Present address: Sanford-Burnham Medical Research Institute, Program of Development and Aging, La Jolla, CA 92037.

3Present address: Division of Molecular and Life Sciences/I-BIO/World Class University Program IT Convergence Engineering, Pohang University of Science & Technology, Pohang, 790-784 South Korea.

The authors declare no conflicts of interest.

Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE20148).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1002575107/-/DCSupplemental.

4To whom correspondence should be addressed. E-mail: cynthia.kenyon{at}ucsf.edu.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism.
G. J. Stout, E. C. A. Stigter, P. B. Essers, K. W. Mulder, A. Kolkman, D. S. Snijders, N. J. F. van den Broek, M. C. Betist, H. C. Korswagen, A. W. MacInnes, et al. (2014)
Mol Syst Biol 9, 679
   Abstract »    Full Text »    PDF »
Nicotinamide Phosphoribosyltransferase Is Required for the Calorie Restriction-Mediated Improvements in Oxidative Stress, Mitochondrial Biogenesis, and Metabolic Adaptation.
J. Song, S.-F. Ke, C.-C. Zhou, S.-L. Zhang, Y.-F. Guan, T.-Y. Xu, C.-Q. Sheng, P. Wang, and C.-Y. Miao (2014)
J Gerontol A Biol Sci Med Sci 69, 44-57
   Abstract »    Full Text »    PDF »
The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans.
M. Safra, S. Ben-Hamo, C. Kenyon, and S. Henis-Korenblit (2013)
J. Cell Sci. 126, 4136-4146
   Abstract »    Full Text »    PDF »
Pharmacological assays reveal age-related changes in synaptic transmission at the Caenorhabditis elegans neuromuscular junction that are modified by reduced insulin signalling.
B. Mulcahy, L. Holden-Dye, and V. O'Connor (2013)
J. Exp. Biol. 216, 492-501
   Abstract »    Full Text »    PDF »
Organismal regulation of XBP-1-mediated unfolded protein response during development and immune activation.
J. Sun, Y. Liu, and A. Aballay (2012)
EMBO Rep. 13, 855-860
   Abstract »    Full Text »    PDF »
Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy.
R. L. Vidal, A. Figueroa, F. A. Court, P. Thielen, C. Molina, C. Wirth, B. Caballero, R. Kiffin, J. Segura-Aguilar, A. M. Cuervo, et al. (2012)
Hum. Mol. Genet. 21, 2245-2262
   Abstract »    Full Text »    PDF »
A conserved cell growth cycle can account for the environmental stress responses of divergent eukaryotes.
N. Slavov, E. M. Airoldi, A. van Oudenaarden, and D. Botstein (2012)
Mol. Biol. Cell 23, 1986-1997
   Abstract »    Full Text »    PDF »
Gene Categories Differentially Expressed in C. elegans Age-1 Mutants of Extraordinary Longevity: New Insights From Novel Data-Mining Procedures.
R. J. Shmookler Reis, S. Ayyadevara, W. A. Crow, T. Lee, and R. R. Delongchamp (2012)
J Gerontol A Biol Sci Med Sci 67A, 366-375
   Abstract »    Full Text »    PDF »
Heightened Induction of Proapoptotic Signals in Response to Endoplasmic Reticulum Stress in Primary Fibroblasts from a Mouse Model of Longevity.
A. A. Sadighi Akha, J. M. Harper, A. B. Salmon, B. A. Schroeder, H. M. Tyra, D. T. Rutkowski, and R. A. Miller (2011)
J. Biol. Chem. 286, 30344-30351
   Abstract »    Full Text »    PDF »
Cellular stress response pathways and ageing: intricate molecular relationships.
N. Kourtis and N. Tavernarakis (2011)
EMBO J. 30, 2520-2531
   Abstract »    Full Text »    PDF »
Aging as an Event of Proteostasis Collapse.
R. C. Taylor and A. Dillin (2011)
Cold Spring Harb Perspect Biol 3, a004440
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882