Abstract
The Caenorhabditis elegans von Hippel-Lindau tumor suppressor homolog VHL-1 is a cullin E3 ubiquitin ligase that negatively regulates the hypoxic response by promoting ubiquitination and degradation of the hypoxic response transcription factor HIF-1. Here, we report that loss of VHL-1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF-1 was epistatic to VHL-1, indicating that HIF-1 acts downstream of VHL-1 to modulate aging and proteotoxicity. VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Aging / physiology*
- Amyloid beta-Peptides / toxicity
- Animals
- Caenorhabditis elegans / genetics
- Caenorhabditis elegans / metabolism
- Caenorhabditis elegans / physiology*
- Caenorhabditis elegans Proteins / genetics
- Caenorhabditis elegans Proteins / metabolism*
- Caloric Restriction
- Cullin Proteins / genetics
- Cullin Proteins / metabolism*
- Female
- Fertility
- Gene Expression Regulation
- Homeostasis
- Insulin / metabolism
- Longevity / physiology
- Male
- Models, Animal
- Oxygen / physiology*
- Peptides / toxicity
- Proteasome Endopeptidase Complex / metabolism*
- RNA Interference
- Receptor, Insulin / genetics
- Receptor, Insulin / metabolism
- Signal Transduction
- Transcription Factors / genetics
- Transcription Factors / metabolism*
- Ubiquitination
Substances
- Amyloid beta-Peptides
- Caenorhabditis elegans Proteins
- Cullin Proteins
- Egl-9 protein, C elegans
- HIF-1 protein, C elegans
- Insulin
- Peptides
- Transcription Factors
- VHL-1 protein, C elegans
- polyglutamine
- DAF-2 protein, C elegans
- Receptor, Insulin
- Proteasome Endopeptidase Complex
- Oxygen