Regulation of Caenorhabditis elegans lifespan by a proteasomal E3 ligase complex.
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.
Ghazi
Arjumand
A
Department of Biochemistry and Biophysics, University of California, Mission Bay Genentech Hall, 600 16th Street, San Francisco, CA 94158, USA.
Henis-Korenblit
Sivan
S
Kenyon
Cynthia
C
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex