atf-6;daf-2

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Genetic mutants with atf-6, daf-2 alterations

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

Lifespan (days)
30.0
Lifespan change (compared to wild type)
47.06%
Phenotype
Inactivation of atf-6 did not shorten the lifespan of daf-2 mutants.
Lifespan comparisons
Double mutant atf-6(RNAi);daf-2(e1368) has a lifespan of 30.0 days, while single mutant atf-6(RNAi) has a lifespan of 15.7 days, single mutant daf-2(e1368) has a lifespan of 32.3 days and wild type has a lifespan of 20.4 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
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.

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

Lifespan (days)
39.9
Lifespan change (compared to wild type)
95.59%
Phenotype
Inactivation of atf-6 did not shorten the lifespan of daf-2 mutants.
Lifespan comparisons
Double mutant atf-6(RNAi);daf-2(e1370) has a lifespan of 39.9 days, while single mutant atf-6(RNAi) has a lifespan of 15.7 days, single mutant daf-2(e1370) has a lifespan of 44.6 days and wild type has a lifespan of 20.4 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
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.

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

Lifespan (days)
42.7
Lifespan change (compared to wild type)
115.66%
Phenotype
Inactivation of atf-6 did not shorten the lifespan of daf-2 mutants.
Lifespan comparisons
Double mutant atf-6(ok551);daf-2(e1370) has a lifespan of 42.7 days, while single mutant atf-6(ok551) has a lifespan of 18.5 days, single mutant daf-2(e1370) has a lifespan of 41.5 days and wild type has a lifespan of 19.8 days.
Type of interaction
See methods
Enhancer, opposite lifespan effects
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: atf-6 daf-2

Entrez ID
Symbol
GenAge
Wormbase ID

181405
atf-6
View on GenAge (atf-6)
WBGene00000222

ATF (cAMP-dependent transcription factor) family

Locus: CELE_F45E6.2

Wormbase description: atf-6 is an ortholog of mammalian ATF6alpha, a proximal sensor required for the unfolded protein response (UPR) in the endoplasmic reticulum (ER); ATF6alpha is a transmembrane protein, with a bZIP transcription factor domain in its cytosolic amino terminus that is released and activated by proteolytic cleavage upon ER stress; either ire-1 or xbp-1 deletions are synthetically lethal with atf-6 or pek-1 deletions, producing arrest in L2 larvae; RNAi of Y56A3A.2 (a S2P protease homolog) is synthetically lethal with ire-1(RNAi), consistent with the hypothesis that Y56A3A.2 cleaves ATF-6; atf-6 regulates few genes that are transcriptionally induced by UPR, but regulates roughly one-quarter of genes that require UPR constitutively; pdr-1 transcripts are strongly upregulated in a atf-6(ok551) mutant background, but atf-6(ok551);pdr-1(lg103) double mutants have a grossly normal phenotype ; atf-6 is dispensable for proper localization of GLR-1 glutamate receptors.

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.

Orthologs of atf-6;daf-2 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Atf6;Insr
Mus musculus	Atf6;Igf1r
Mus musculus	Atf6;Insrr

Orthologs of atf-6 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Atf6

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