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Published online on March 28, 2007, 10.1073/pnas.0700638104
PNAS | April 3, 2007 | vol. 104 | no. 14 | 5947-5952


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BIOLOGICAL SCIENCES / GENETICS
Regulation of Caenorhabditis elegans lifespan by a proteasomal E3 ligase complex

Arjumand Ghazi, Sivan Henis-Korenblit, and Cynthia Kenyon{dagger}

Department of Biochemistry and Biophysics, University of California, Mission Bay Genentech Hall, 600 16th Street, San Francisco, CA 94158

Contributed by Cynthia Kenyon, January 25, 2007 (received for review January 4, 2007)

The proteasome maintains cellular homeostasis by degrading oxidized and damaged proteins, a function known to be impaired during aging. The proteasome also acts in a regulatory capacity through E3 ligases to mediate the spatially and temporally controlled breakdown of specific proteins that impact biological processes. We have identified components of a Skp1-Cul1-F-Box E3 ligase complex that are required for the extended lifespan of Caenorhabditis elegans insulin/insulin-like growth factor-1-signaling (IIS) mutants. The CUL-1 complex functions in postmitotic, adult somatic tissues of IIS mutants to enhance longevity. Reducing IIS function leads to the nuclear accumulation of the DAF-16/FOXO transcription factor, which extends lifespan by regulating downstream longevity genes. These CUL-1 complex genes act, at least in part, by promoting the transcriptional activity of DAF-16/FOXO. Together, our findings describe a role for an important cellular pathway, the proteasomal pathway, in the genetic determination of lifespan.

aging | proteasome | ubiquitin | daf-2 | insulin

Author contributions: A.G. and S.H.-K. contributed equally to this work; A.G., S.H.-K., and C.K. designed research; A.G. and S.H.-K. performed research; A.G., S.H.-K., and C.K. analyzed data; and A.G. and C.K. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0700638104/DC1.

{dagger}To whom correspondence should be addressed. E-mail: ckenyon{at}biochem.ucsf.edu

© 2007 by The National Academy of Sciences of the USA


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