Publication Date:
2009-06-26
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746748/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746748/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carrano, Andrea C -- Liu, Zheng -- Dillin, Andrew -- Hunter, Tony -- AG 027463/AG/NIA NIH HHS/ -- AG 032560/AG/NIA NIH HHS/ -- CA 14195/CA/NCI NIH HHS/ -- CA 54418/CA/NCI NIH HHS/ -- CA 82683/CA/NCI NIH HHS/ -- DK 070696/DK/NIDDK NIH HHS/ -- P01 CA054418/CA/NCI NIH HHS/ -- P01 CA054418-110010/CA/NCI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 CA014195-35/CA/NCI NIH HHS/ -- R01 AG027463/AG/NIA NIH HHS/ -- R01 AG027463-01A2/AG/NIA NIH HHS/ -- R01 CA082683/CA/NCI NIH HHS/ -- R01 CA082683-07/CA/NCI NIH HHS/ -- R01 CA082683-08/CA/NCI NIH HHS/ -- R01 DK070696/DK/NIDDK NIH HHS/ -- R01 DK070696-04/DK/NIDDK NIH HHS/ -- R21 AG032560/AG/NIA NIH HHS/ -- R21 AG032560-01/AG/NIA NIH HHS/ -- England -- Nature. 2009 Jul 16;460(7253):396-9. doi: 10.1038/nature08130. Epub 2009 Jun 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19553937" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Animals, Genetically Modified
;
Caenorhabditis elegans/genetics/*physiology
;
Caenorhabditis elegans Proteins/genetics/*metabolism
;
*Caloric Restriction
;
DNA-Binding Proteins/metabolism
;
Heat-Shock Response
;
Ligases/genetics/*metabolism
;
Longevity/*physiology
;
Protein Binding
;
Receptors, Nicotinic/genetics/metabolism
;
Trans-Activators/genetics/metabolism
;
Transcription Factors/metabolism
;
Ubiquitin-Protein Ligases/genetics/*metabolism
;
Ubiquitination/*physiology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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