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

PNAS, 25 May 2010
Vol. 107, Issue 21, p. 9730-9735
DOI: 10.1073/pnas.1002575107

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

  1. Sivan Henis-Korenblit1,
  2. Peichuan Zhang,
  3. Malene Hansen2,
  4. Mark McCormick,
  5. Seung-Jae Lee3,
  6. Michael Cary, and
  7. Cynthia Kenyon4
  1. Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158
  • 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.

  1. 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.

  • aging
  • daf-2
  • insulin signaling
  • unfolded protein response

Footnotes

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

  • 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.

    Citation:

    S. Henis-Korenblit, P. Zhang, M. Hansen, M. McCormick, S.-J. Lee, M. Cary, and C. Kenyon, Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. PNAS 107, 9730-9735 (2010).

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