daf-16;wwp-1

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Genetic mutants with daf-16, wwp-1 alterations

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
20
Diet
HT115
Lifespan (days)
21.0
Lifespan change (compared to wild type)
16.02%
Phenotype
RNAi reduction of daf-16 did not suppress the increased longevity of worms overexpressing wwp-1.
Lifespan comparisons
Double mutant daf-16(RNAi);wwp-1(OE) has a lifespan of 21.0 days, while single mutant daf-16(RNAi) has a lifespan of 17.2 days, single mutant wwp-1(OE) has a lifespan of 22.5 days and wild type has a lifespan of 18.1 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Carrano AC et al., 2009, A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature. 460(7253):396-9 19553937 Click here to select all mutants from this PubMed ID in the graph
Abstract
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.

Temperature °C
20
Diet
HT115
Lifespan (days)
21.1
Lifespan change (compared to wild type)
8.76%
Phenotype
RNAi reduction of daf-16 did not suppress the increased longevity of worms overexpressing wwp-1.
Lifespan comparisons
Double mutant daf-16(RNAi);wwp-1(OE) has a lifespan of 21.1 days, while single mutant daf-16(RNAi) has a lifespan of 18.6 days, single mutant wwp-1(OE) has a lifespan of 21.5 days and wild type has a lifespan of 19.4 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Carrano AC et al., 2009, A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature. 460(7253):396-9 19553937 Click here to select all mutants from this PubMed ID in the graph
Abstract
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.

Search genes: daf-16 wwp-1

Entrez ID
Symbol
GenAge
Wormbase ID

172981
daf-16
View on GenAge (daf-16)
WBGene00000912

Forkhead box protein O;hypothetical protein

Locus: CELE_R13H8.1

Wormbase description: daf-16 encodes the sole C. elegans forkhead box O (FOXO) homologue; DAF-16 functions as a transcription factor that acts in the insulin/IGF-1-mediated signaling (IIS) pathway that regulates dauer formation, longevity, fat metabolism, stress response, and innate immunity; DAF-16 regulates these various processes through isoform-specific expression, isoform-specific regulation by different AKT kinases, and differential regulation of target genes; DAF-16 can interact with the CBP-1 transcription cofactor in vitro, and interacts genetically with other genes in the insulin signaling and with daf-12, which encodes a nuclear hormone receptor; DAF-16 is activated in response to DNA damage during development and co-regulated by EGL-27, alleviates DNA-damage-induced developmental arrest by inducing DAF-16-associated element (DAE)-regulated genes; DAF-16 is broadly expressed but displays isoform-specific tissue enrichment; DAF-16 localizes to both the cytoplasm and the nucleus, with the ratio between the two an important regulator of function.

Entrez ID
Symbol
GenAge
Wormbase ID

171647
wwp-1
View on GenAge (wwp-1)
WBGene00007009

E3 ubiquitin-protein ligase;WW domain Protein (E3 ubiquitin ligase)

Locus: CELE_Y65B4BR.4

Wormbase description: wwp-1 encodes, by alternative splicing, two isoforms of a putative E3 ubiquitin ligase orthologous to budding yeast Rsp5, Drosophila SU(DX), and human WWP1 (OMIM:602307) and WWP2 (OMIM:602308); WWP-1 is required for proteolysis of the intracellular LIN-12 domain in primary ventral precursor cells, and for protection of germ cells against ionizing radiation or camptothecin, as well as for normal acetylcholine neurotransmission, axonal guidance and fasciculation, patterning of the ventral nerve cord, locomotion, fat content, and late embryonic morphogenesis; in UV-irradiated nondauer larvae, WWP-1 stimulates the proteolysis of AMA-1; although WWP-1's is normally blocked from fully activating AMA-1 proteolysis by XPA-1/RAD-3, it also cooperates with XPA-1/RAD-3 to protect worms from UV-irradiation; WWP-1 is expressed in many neurons (cholinergic and GABAergic motor neurons, head, tail, body, and nerve cords), in larval and adult pharynx, intestine, renal gland cells and rectal epithelium, and in adult vulval muscle, body wall muscle, and coelomocytes; WWP-1 contains an N-terminal C2 domain, four central WW repeats and a C-terminal HECT ubiquitin ligase domain; WWP-1 binds UBC-18 in yeast two-hybrid assays, but is not required for UBC-18's activity in pharyngeal development.

Orthologs of daf-16;wwp-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6;Wwp1
Mus musculus	Foxo6;Itch
Mus musculus	Foxo6;Wwp2
Mus musculus	Foxo1;Wwp1
Mus musculus	Foxo1;Itch
Mus musculus	Foxo1;Wwp2
Mus musculus	Foxo4;Wwp1
Mus musculus	Foxo4;Itch
Mus musculus	Foxo4;Wwp2
Mus musculus	Foxo3;Wwp1
Mus musculus	Foxo3;Itch
Mus musculus	Foxo3;Wwp2
Mus musculus	Wwp1;Foxo6
Mus musculus	Wwp1;Foxo1
Mus musculus	Wwp1;Foxo4
Mus musculus	Wwp1;Foxo3
Mus musculus	Itch;Foxo6
Mus musculus	Itch;Foxo1
Mus musculus	Itch;Foxo4
Mus musculus	Itch;Foxo3
Mus musculus	Wwp2;Foxo6
Mus musculus	Wwp2;Foxo1
Mus musculus	Wwp2;Foxo4
Mus musculus	Wwp2;Foxo3

Orthologs of daf-16 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6
Mus musculus	Foxo1
Mus musculus	Foxo4
Mus musculus	Foxo3

Orthologs of wwp-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Su(dx)
Mus musculus	Wwp1
Mus musculus	Itch
Mus musculus	Wwp2