Regulation of Caenorhabditis elegans lifespan by a proteasomal E3 ligase complex
Open accessAbstract
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.
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Mutations in the genes of the CUL-1 E3 ligase complex shorten the extended lifespan of different insulin signaling C. elegans mutants.
“mutations in the genes of the CUL-1 E3 ligase complex shorten the extended lifespan of different insulin signaling C. elegans mutants (Ghazi et al., 2007)”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Ghazi et al., 2007
The Results report that RNAi depletion of cul-1 and skr-1/2 shortened the extended lifespan of several daf-2 mutant strains, and that a lin-23 mutation reduced lifespan extension in daf-2 mutants. The claim captures the lifespan finding but overstates the mutation evidence: the paper tested mutations in one CUL-1 complex gene, while it used RNAi to reduce the others. (LLM, conf=0.86)
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- NoteAddedinProof. Whilethis study was in press, Li et al . (39) published results identifying an E3 ligase that affects aging in an opposite fashion.
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- Authors
- Ghazi, A., Henis-Korenblit, S., & Kenyon, C.
- Affiliations
- University of California, San Francisco (US)
- Department of Biochemistry and Biophysics, University of California, Mission Bay Genentech Hall, 600 16th Street, San Francisco, CA 94158
- Corresponding author
- Kenyon, Cynthia
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-04-03
- Volume
- 104
- Issue
- 14
- Pages
- 5947-5952
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1851597
- OpenAlex
- W2047102030
- Cited by
- 134
- References
- 40
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 8 · 2022: 10 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 11 · 2015: 6 · 2014: 10 · 2013: 7 · 2012: 10
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Larry L. Hillblom Foundation
- National Institutes of Health
- National Institute on Aging (R01AG011816)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- Caenorhabditis elegans, lifespan extension, proteasome, E3 ubiquitin ligase, insulin/IGF-1 signaling, DAF-16/FOXO, aging, protein degradation, longevity genes, transcriptional regulation
- MeSH terms
- Animals, Gene Expression Regulation, Longevity, Caenorhabditis elegans, Animals, Genetically Modified, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex
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