daf-2;fem-1;fer-15;ire-1

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Genetic mutants with daf-2, fem-1, fer-15, ire-1 alterations

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

Lifespan (days)
20.9
Lifespan comparisons
Quadruple mutant daf-2(mu150);fem-1(hc17);fer-15(b26);ire-1(RNAi) has a lifespan of 20.9 days, while triple mutant daf-2(mu150);fem-1(hc17);fer-15(b26) has a lifespan of 35.6 days.
Citation
View abstract
Henis-Korenblit S et al., 2010, Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A. 107(21):9730-5 20460307 Click here to select all mutants from this PubMed ID in the graph
Abstract
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.

Lifespan (days)
19.2
Lifespan comparisons
Quadruple mutant daf-2(mu150);fem-1(hc17);fer-15(b26);ire-1(RNAi) has a lifespan of 19.2 days, while triple mutant daf-2(mu150);fem-1(hc17);fer-15(b26) has a lifespan of 34.8 days.
Citation
View abstract
Henis-Korenblit S et al., 2010, Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A. 107(21):9730-5 20460307 Click here to select all mutants from this PubMed ID in the graph
Abstract
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.

Lifespan (days)
19.7
Lifespan comparisons
Quadruple mutant daf-2(mu150);fem-1(hc17);fer-15(b26);ire-1(RNAi) has a lifespan of 19.7 days, while triple mutant daf-2(mu150);fem-1(hc17);fer-15(b26) has a lifespan of 31.9 days.
Citation
View abstract
Henis-Korenblit S et al., 2010, Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci U S A. 107(21):9730-5 20460307 Click here to select all mutants from this PubMed ID in the graph
Abstract
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.

Search genes: daf-2 fem-1 fer-15 ire-1 daf-2;fem-1;fer-15;ire-1

Entrez ID
Symbol
GenAge
Wormbase ID

175410
daf-2
View on GenAge (daf-2)
WBGene00000898

Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein

Locus: CELE_Y55D5A.5

Wormbase description: daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle.

Entrez ID
Symbol
GenAge
Wormbase ID

177335
fem-1
View on GenAge (fem-1)
WBGene00001411

Sex-determining protein fem-1

Locus: CELE_F35D6.1

Wormbase description: The fem-1 gene encodes an ankyrin repeat-containing protein orthologous to human FEM1A and is required for masculinization of germline and somatic tissues; FEM-1 is widely expressed and functions as a second messenger in the sex determination pathway, connecting the membrane protein TRA-2A to the transcription factor TRA-1A which it negatively regulates; FEM-1 may also play a role in apoptosis, as it is a substrate for the CED-3 protease and can induce apoptosis when overexpressed in mammalian cells.

Symbol
GenAge

fer-15
View on GenAge (fer-15)

No gene information for fer-15

Entrez ID
Symbol
GenAge
Wormbase ID

174305
ire-1
View on GenAge (ire-1)
WBGene00002147

IRE1 kinase related;Serine/threonine-protein kinase

Locus: CELE_C41C4.4

Wormbase description: ire-1 encodes a transmembrane serine/threonine protein kinase and site-specific endoribonuclease orthologous to Saccharomyces cerevisiae inositol-requiring 1 protein kinase (Ire1) and human endoplasmic reticulum-to-nucleus signaling 1 (ERN1, OMIM:604033); IRE-1 is required for the unfolded protein response (UPR) that counteracts cellular stress induced by accumulation of unfolded proteins in the endoplasmic reticulum (ER); in response to ER stress, IRE-1 cleaves xbp-1 mRNA to produce transcriptionally active XBP-1 that positively regulates UPR gene expression in order to maintain ER homeostasis.

Orthologs of daf-2;fem-1;fer-15;ire-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Insr;Ern1
Mus musculus	Insr;Ern2
Mus musculus	Igf1r;Ern1
Mus musculus	Igf1r;Ern2
Mus musculus	Insrr;Ern1
Mus musculus	Insrr;Ern2

Orthologs of daf-2 in SynergyAge

Show in SynergyAge
Species	Gene
Drosophila melanogaster	InR

Not in SynergyAge
Species	Gene
Mus musculus	Insr
Mus musculus	Igf1r
Mus musculus	Insrr

Orthologs of fem-1 in SynergyAge

Show in SynergyAge
Species	Gene

Orthologs of fer-15 in SynergyAge

Show in SynergyAge
Species	Gene

Orthologs of ire-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Ire1
Mus musculus	Ern1
Mus musculus	Ern2