1. Proteasomal regulation of the hypoxic response modulates aging in C. elegans.
- Author
-
Mehta R, Steinkraus KA, Sutphin GL, Ramos FJ, Shamieh LS, Huh A, Davis C, Chandler-Brown D, and Kaeberlein M
- Subjects
- Amyloid beta-Peptides toxicity, Animals, Caenorhabditis elegans genetics, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Caloric Restriction, Cullin Proteins genetics, Female, Fertility, Gene Expression Regulation, Homeostasis, Insulin metabolism, Longevity physiology, Male, Models, Animal, Peptides toxicity, RNA Interference, Receptor, Insulin genetics, Receptor, Insulin metabolism, Signal Transduction, Transcription Factors genetics, Ubiquitination, Aging physiology, Caenorhabditis elegans physiology, Caenorhabditis elegans Proteins metabolism, Cullin Proteins metabolism, Oxygen physiology, Proteasome Endopeptidase Complex metabolism, Transcription Factors metabolism
- 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.
- Published
- 2009
- Full Text
- View/download PDF