A conserved ubiquitination pathway determines longevity in response to diet restriction.
Dietary restriction extends longevity in diverse species, suggesting that there is a conserved mechanism for nutrient regulation and prosurvival responses. Here we show a role for the HECT (homologous to E6AP carboxy terminus) E3 ubiquitin ligase WWP-1 as a positive regulator of lifespan in Caenorhabditis elegans in response to dietary restriction. We find that overexpression of wwp-1 in worms extends lifespan by up to 20% under conditions of ad libitum feeding. This extension is dependent on the FOXA transcription factor pha-4, and independent of the FOXO transcription factor daf-16. Reduction of wwp-1 completely suppresses the extended longevity of diet-restricted animals. However, the loss of wwp-1 does not affect the long lifespan of animals with compromised mitochondrial function or reduced insulin/IGF-1 signalling. Overexpression of a mutant form of WWP-1 lacking catalytic activity suppresses the increased lifespan of diet-restricted animals, indicating that WWP-1 ubiquitin ligase activity is essential for longevity. Furthermore, we find that the E2 ubiquitin conjugating enzyme, UBC-18, is essential and specific for diet-restriction-induced longevity. UBC-18 interacts with WWP-1 and is required for the ubiquitin ligase activity of WWP-1 and the extended longevity of worms overexpressing wwp-1. Taken together, our results indicate that WWP-1 and UBC-18 function to ubiquitinate substrates that regulate diet-restriction-induced longevity.
Carrano
Andrea C
AC
Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Liu
Zheng
Z
Dillin
Andrew
A
Hunter
Tony
T
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D031204:Caloric Restriction; D004268:DNA-Binding Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C487508:Eat-2 protein, C elegans; C113277:Pha-4 protein, C elegans; D011978:Receptors, Nicotinic; D015534:Trans-Activators; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; C413402:wwp-1 protein, C elegans; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C476242:Ubc-18 protein, C elegans