pha-4;wwp-1

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Genetic mutants with pha-4, 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)
17.5
Lifespan change (compared to wild type)
-6.42%
Phenotype
RNAi reduction of pha-4 suppressed the increased longevity of worms overexpressing wwp-1
Lifespan comparisons
Double mutant pha-4(RNAi);wwp-1(OE) has a lifespan of 17.5 days, while single mutant pha-4(RNAi) has a lifespan of 16.7 days, single mutant wwp-1(OE) has a lifespan of 23.1 days and wild type has a lifespan of 18.7 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)
16.4
Lifespan change (compared to wild type)
-12.30%
Phenotype
RNAi reduction of pha-4 suppressed the increased longevity of worms overexpressing wwp-1
Lifespan comparisons
Double mutant pha-4(RNAi);wwp-1(OE) has a lifespan of 16.4 days, while single mutant pha-4(RNAi) has a lifespan of 15.6 days, single mutant wwp-1(OE) has a lifespan of 21.1 days and wild type has a lifespan of 18.7 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)
17.1
Lifespan change (compared to wild type)
-8.56%
Phenotype
RNAi reduction of pha-4 suppressed the increased longevity of worms overexpressing wwp-1
Lifespan comparisons
Double mutant pha-4(RNAi);wwp-1(OE) has a lifespan of 17.1 days, while single mutant pha-4(RNAi) has a lifespan of 16.3 days, single mutant wwp-1(OE) has a lifespan of 21.5 days and wild type has a lifespan of 18.7 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: pha-4 wwp-1

Entrez ID
Symbol
GenAge
Wormbase ID

180357
pha-4
View on GenAge (pha-4)
WBGene00004013

Defective pharyngeal development protein 4

Locus: CELE_F38A6.1

Wormbase description: pha-4 encodes a FoxA transcription factor; during embryonic development, PHA-4 functions as an organ identity gene whose activity is necessary and sufficient for development of the pharynx/foregut; in addition, PHA-4 plays a key role in regulation of diet-restriction-induced longevity in adult animals; PHA-4 expression begins early in embryogenesis and is seen in pharyngeal and intestinal cells (foregut and midgut); PHA-4 is also expressed later in the developing somatic gonad.

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 pha-4;wwp-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	FoxK;Su(dx)
Mus musculus	Su(dx);FoxK

Orthologs of pha-4 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	FoxK

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