DAF-16 is a forkhead box transcription factor (FOXO) that is the primary downstream effector of the insulin/IGF-1-like signaling (IIS) pathway in C. elegans. It functions as a key regulator of longevity, stress resistance, dauer larval development, innate immunity, and metabolism. Under conditions of reduced IIS (e.g., daf-2 mutants), DAF-16 translocates from the cytoplasm to the nucleus where it activates transcription of target genes involved in stress response, metabolism, and longevity. DAF-16 is negatively regulated by AKT-1, AKT-2, and SGK-1 kinases, which phosphorylate DAF-16 and promote cytoplasmic retention via 14-3-3 protein binding (FTT-2). Multiple DAF-16 isoforms exist (a, b, c, d, e, f, h) with distinct expression patterns and potentially different functions in lifespan modulation. The intestine is the primary tissue for DAF-16-dependent longevity signaling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: DAF-16 is a well-characterized forkhead transcription factor that regulates RNA polymerase II-dependent transcription. This annotation is supported by phylogenetic analysis showing conservation across FOXO family members. The UniProt entry confirms "Forkhead-type transcription factor" function and binding to the DBE element (TTGTTTAC) in target gene promoters. Reason: Core molecular function of DAF-16 as a transcription factor is extensively documented. IBA annotation is consistent with experimental evidence showing DAF-16 binds DNA and activates transcription of target genes [PMID:11124266]. Supporting Evidence: PMID:11124266 In vitro, interaction of AKT- phosphorylated DAF-16 with 14-3-3 prevents DAF-16 binding to its target site in the insulin-like growth factor binding protein-1 gene, the insulin response element file:worm/daf-16/daf-16-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: DAF-16 shuttles between cytoplasm and nucleus, with nuclear localization being essential for its transcriptional activity. This IBA annotation is well-supported by extensive experimental evidence. Reason: Nuclear localization is fundamental to DAF-16 function. Multiple publications demonstrate nuclear accumulation under stress conditions and in daf-2 mutants [PMID:11381260, PMID:11747825, PMID:21531333]. Supporting Evidence: PMID:11381260 Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei PMID:11747825 Environmental stresses, such as starvation, heat, and oxidative stress, cause rapid nuclear localization of DAF-16 |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: DAF-16 regulates transcription of numerous target genes involved in stress response, longevity, and metabolism. This IBA annotation accurately reflects DAF-16's core biological process. Reason: Well-supported by experimental evidence. DAF-16 activates transcription of target genes like sod-3, rpn-6.1, and represses others [PMID:22922647, PMID:11747821]. Supporting Evidence: PMID:22922647 increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16 |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: DAF-16 binds to specific DNA sequences (DAF-16 binding element, DBE: TTGTTTAC) in target gene promoters. This is a core molecular function of the forkhead domain. [PMID:19506556] Reason: Sequence-specific DNA binding is central to DAF-16 function. The forkhead domain mediates binding to DBE elements in target promoters [PMID:11124266]. Supporting Evidence: PMID:11124266 In vitro, interaction of AKT- phosphorylated DAF-16 with 14-3-3 prevents DAF-16 binding to its target site in the insulin-like growth factor binding protein-1 gene, the insulin response element |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 functions as both transcriptional activator and repressor depending on context. It activates genes like sod-3 and rpn-6.1, supporting this annotation. Reason: DAF-16 activates transcription of many longevity and stress response genes. The IEA annotation is consistent with experimental data [PMID:11124266, PMID:22922647]. Supporting Evidence: PMID:11124266 In HepG2 cells, insulin signaling to PI 3-kinase/AKT inhibits the ability of a GAL4 DNA binding domain/DAF-16 fusion protein to activate transcription via the insulin-like growth factor binding protein-1-insulin response element, but not the GAL4 DNA binding site, which suggests that insulin inhibits the interaction of DAF-16 with its cognate DNA site |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: DAF-16 is involved in C. elegans innate immunity, regulating defense responses to bacterial pathogens. This annotation is supported by experimental evidence. Reason: DAF-16's role in immunity is well-established. It regulates immune response genes and contributes to pathogen resistance [PMID:17096597, PMID:19454349]. Supporting Evidence: PMID:17096597 p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans PMID:19454349 Conditioning requires... the insulin/IGFR pathway, which regulates lifespan |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: General DNA binding activity is intrinsic to DAF-16's function as a forkhead transcription factor. This is a broader term than the more specific sequence- specific binding annotations. Reason: DNA binding is fundamental to DAF-16 function. The forkhead domain enables DNA binding, and this is consistent with more specific annotations. Supporting Evidence: PMID:11124266 In vitro, interaction of AKT- phosphorylated DAF-16 with 14-3-3 prevents DAF-16 binding to its target site in the insulin-like growth factor binding protein-1 gene, the insulin response element |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: DAF-16 is a DNA-binding transcription factor, a core function supported by InterPro domain annotation (forkhead domain). Reason: This is the fundamental molecular function of DAF-16. IEA from InterPro is consistent with experimental evidence. Supporting Evidence: PMID:11124266 a GAL4 DNA binding domain/DAF-16 fusion protein to activate transcription |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization is essential for DAF-16 transcriptional activity. Duplicate of IBA annotation with same term. Reason: Consistent with IBA and experimental evidence. DAF-16 translocates to nucleus under stress and low IIS conditions [PMID:11381260]. Supporting Evidence: PMID:11381260 Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: DAF-16 is retained in the cytoplasm when IIS is active, through phosphorylation and 14-3-3 protein binding. Reason: Cytoplasmic localization under fed/unstressed conditions is well-documented. AKT phosphorylation promotes 14-3-3 binding and cytoplasmic retention [PMID:11381260, PMID:17098225]. Supporting Evidence: PMID:17098225 FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 by sequestering it in the cytoplasm |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: DAF-16 participates in DNA-templated transcription as a transcription factor. This is a parent term of more specific transcription regulation terms. Reason: Consistent with DAF-16's role as a transcription factor regulating gene expression. Supporting Evidence: PMID:11124266 a GAL4 DNA binding domain/DAF-16 fusion protein to activate transcription |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: DAF-16 regulates transcription of target genes. This IEA from InterPro is consistent with its forkhead domain function. Reason: Core function of DAF-16. Regulates transcription of numerous target genes involved in longevity, stress response, and metabolism. Supporting Evidence: PMID:22922647 increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16 |
| GO:0008286 insulin receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 is the major downstream effector of the insulin/IGF-1 signaling pathway in C. elegans. This is a core biological process annotation. Reason: Central role of DAF-16 in IIS pathway is extensively documented. DAF-16 is negatively regulated by DAF-2/insulin receptor signaling via AKT kinases [PMID:11381260, PMID:11747821]. Supporting Evidence: PMID:11381260 The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2 PMID:11747821 daf-2 insulin signaling, via AKT kinases, negatively regulates DAF-16 by controlling its nuclear localization |
| GO:0008340 determination of adult lifespan | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 is essential for lifespan extension in daf-2 mutants and other longevity paradigms. This is a core function of DAF-16. Reason: Longevity regulation is one of the best-characterized functions of DAF-16. Lifespan extension in IIS mutants absolutely requires DAF-16 [PMID:11381260, PMID:11747825]. Supporting Evidence: PMID:11381260 This lifespan extension requires DAF-16, a forkhead/winged-helix transcription factor |
| GO:0009896 positive regulation of catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 regulates proteasome activity and protein catabolism. It activates rpn-6.1 expression to enhance proteasome function. Reason: DAF-16 promotes protein catabolism through upregulation of proteasome components. This is supported by experimental evidence [PMID:22922647, PMID:23770237]. Supporting Evidence: PMID:22922647 increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16 |
| GO:0010883 regulation of lipid storage | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 regulates lipid metabolism and fat storage. daf-2 mutants accumulate fat in a DAF-16-dependent manner. Reason: Lipid storage regulation is a documented DAF-16 function. UniProt notes prmt-1 is required for fat storage in daf-2 mutants [PMID:21531333]. Supporting Evidence: PMID:21531333 prmt-1 is also required for stress tolerance and fat storage but not dauer formation in daf-2 mutants |
| GO:0031349 positive regulation of defense response | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 positively regulates innate immune responses to pathogens. Reason: DAF-16 contributes to pathogen resistance and immune gene expression [PMID:17096597, PMID:19454349]. Supporting Evidence: PMID:19454349 Conditioning requires... the insulin/IGFR pathway, which regulates lifespan |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 mediates responses to oxidative stress, including activation of antioxidant genes like sod-3. Reason: Oxidative stress response is a core DAF-16 function. DAF-16 activates sod-3 and other stress response genes [PMID:15905404, PMID:11747825]. Supporting Evidence: PMID:15905404 BAR-1 was required for the oxidative stress-induced expression of the DAF-16 target gene sod-3 PMID:11747825 Environmental stresses, such as starvation, heat, and oxidative stress, cause rapid nuclear localization of DAF-16 |
| GO:0040015 negative regulation of multicellular organism growth | IEA GO_REF:0000117 | ACCEPT | Summary: Activation of DAF-16 leads to reduced growth and reproduction, as resources are diverted to stress resistance. Reason: DAF-16 activation causes growth trade-offs. DAF-16::GFP transgenic animals grow more slowly but are stress resistant [PMID:11747825]. Supporting Evidence: PMID:11747825 nematodes carrying an integrated DAF-16::GFP transgene grow and reproduce more slowly yet are more stress resistant and longer lived |
| GO:0042594 response to starvation | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 is activated by starvation and mediates starvation responses. Reason: Starvation induces DAF-16 nuclear localization and activation of survival programs [PMID:11747825, PMID:11381260]. Supporting Evidence: PMID:11747825 Environmental stresses, such as starvation, heat, and oxidative stress, cause rapid nuclear localization of DAF-16 |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: DAF-16 binds to specific DNA sequences (DBE: TTGTTTAC) in target promoters. Reason: Sequence-specific binding via forkhead domain is core to DAF-16 function. InterPro annotation consistent with experimental data. Supporting Evidence: PMID:11124266 In vitro, interaction of AKT- phosphorylated DAF-16 with 14-3-3 prevents DAF-16 binding to its target site in the insulin-like growth factor binding protein-1 gene, the insulin response element |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: DAF-16 regulates innate immunity in C. elegans, contributing to pathogen resistance. Reason: Innate immune function is well-documented for DAF-16 [PMID:17096597, PMID:19454349]. Supporting Evidence: PMID:17096597 p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans |
| GO:0050778 positive regulation of immune response | IEA GO_REF:0000117 | ACCEPT | Summary: DAF-16 positively regulates immune response gene expression. Reason: Consistent with DAF-16's role in innate immunity and defense responses [PMID:17096597, PMID:19454349]. Supporting Evidence: PMID:19454349 Conditioning requires... the insulin/IGFR pathway, which regulates lifespan |
| GO:0005515 protein binding | IPI PMID:15068796 C. elegans SGK-1 is the critical component in the Akt/PKB ki... | MODIFY | Summary: This annotation documents DAF-16 interaction with SGK-1, AKT-1, and AKT-2 kinases. These kinases phosphorylate DAF-16 and regulate its activity. Reason: While the protein binding is documented, "protein binding" is too generic. The interactions with AKT-1, AKT-2, and SGK-1 are regulatory phosphorylation events. More specific terms should be used. Proposed replacements: protein kinase binding Supporting Evidence: PMID:15068796 SGK-1 forms a protein complex with the AKT kinases... All three kinases of this complex are able to directly phosphorylate DAF-16/FKHRL1 |
| GO:0005515 protein binding | IPI PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat... | MODIFY | Summary: This annotation documents DAF-16 interaction with SIR-2.1 sirtuin, which promotes DAF-16 activity during stress. Reason: "Protein binding" is too generic. SIR-2.1 is a sirtuin that regulates DAF-16 activity. A more specific term should be considered. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner |
| GO:0005515 protein binding | IPI PMID:16860373 C. elegans 14-3-3 proteins regulate life span and interact w... | MODIFY | Summary: This annotation documents DAF-16 interaction with SIR-2.1 and 14-3-3 proteins. Reason: "Protein binding" is too generic. This represents 14-3-3 binding (GO:0071889) which is already annotated more specifically elsewhere. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:16860373 C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO |
| GO:0005515 protein binding | IPI PMID:18358814 Direct inhibition of the longevity-promoting factor SKN-1 by... | MODIFY | Summary: This annotation documents DAF-16 interaction with AKT-1, AKT-2, and SGK-1. Duplicate of PMID:15068796 annotation. Reason: "Protein binding" is too generic. These are regulatory kinase interactions. Proposed replacements: protein kinase binding Supporting Evidence: PMID:18358814 The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1 |
| GO:0005634 nucleus | NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat... | ACCEPT | Summary: Nuclear localization documented in context of SIR-2.1/14-3-3 regulation. Reason: Consistent with numerous other annotations for nuclear localization. Supporting Evidence: PMID:16777605 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 |
| GO:0005737 cytoplasm | NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat... | ACCEPT | Summary: Cytoplasmic localization documented in context of 14-3-3 sequestration. Reason: Consistent with DAF-16 nucleocytoplasmic shuttling behavior. Supporting Evidence: PMID:16777605 14-3-3 genes are required for the life-span extension conferred by extra copies of sir-2.1 |
| GO:0005737 cytoplasm | NAS PMID:17098225 The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis ... | ACCEPT | Summary: FTT-2 sequesters DAF-16 in the cytoplasm under normal conditions. Reason: Cytoplasmic retention by FTT-2/14-3-3 is well-documented mechanism of DAF-16 regulation. Supporting Evidence: PMID:17098225 FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 by sequestering it in the cytoplasm |
| GO:0010628 positive regulation of gene expression | NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat... | ACCEPT | Summary: DAF-16 activates transcription of target genes. SIR-2.1 and 14-3-3 enhance this activation. Reason: Consistent with DAF-16's role as a transcriptional activator. Supporting Evidence: PMID:16777605 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 |
| GO:0010629 negative regulation of gene expression | NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat... | ACCEPT | Summary: DAF-16 also represses some target genes. Reason: DAF-16 functions as both activator and repressor depending on target gene. Supporting Evidence: PMID:16777605 14-3-3 proteins are also required for SIR-2.1-induced transcriptional activation of DAF-16 |
| GO:0010629 negative regulation of gene expression | NAS PMID:17098225 The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis ... | ACCEPT | Summary: DAF-16 represses some target genes including ins-7 and others. Reason: DAF-16 can repress gene expression in addition to activating genes. Supporting Evidence: PMID:17098225 ftt-2 knock down caused the nuclear accumulation of DAF-16/FOXO... and enhanced the transcriptional activities of DAF-16 |
| GO:0034605 cellular response to heat | NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat... | ACCEPT | Summary: DAF-16 mediates heat stress responses. Heat stress promotes SIR-2.1/DAF-16 interaction. Reason: Heat stress response is a well-documented DAF-16 function [PMID:11381260, PMID:11747825]. Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner |
| GO:0051457 maintenance of protein location in nucleus | NAS PMID:16777605 C. elegans SIR-2.1 interacts with 14-3-3 proteins to activat... | KEEP AS NON CORE | Summary: This annotation appears to describe nuclear retention of DAF-16 following stress-induced nuclear translocation. Reason: While DAF-16 does accumulate in nuclei during stress, this is more about nuclear translocation than maintenance. The term may be slightly imprecise but captures the nuclear accumulation phenotype. Supporting Evidence: PMID:16777605 Following heat stress, SIR-2.1 can bind DAF-16 in a 14-3-3-dependent manner |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:11124266 Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA ... | ACCEPT | Summary: Direct demonstration that DAF-16 binds to specific DNA sequences in target gene promoters. This is the original key paper on DAF-16 DNA binding. Reason: Core molecular function demonstrated by direct assay. DAF-16 binds to the insulin response element [PMID:11124266]. Supporting Evidence: PMID:11124266 In vitro, interaction of AKT- phosphorylated DAF-16 with 14-3-3 prevents DAF-16 binding to its target site in the insulin-like growth factor binding protein-1 gene, the insulin response element |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:19506556 A soma-to-germline transformation in long-lived Caenorhabdit... | ACCEPT | Summary: ChIP experiments demonstrating DAF-16 binding to chromatin in germline-less long-lived mutants. Reason: Direct evidence of DAF-16 DNA binding by ChIP analysis. Supporting Evidence: PMID:19506556 A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants |
| GO:0005634 nucleus | IDA PMID:11124266 Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA ... | ACCEPT | Summary: Nuclear localization demonstrated in this foundational paper on DAF-16 regulation. Reason: Direct experimental evidence of nuclear localization. Supporting Evidence: PMID:11124266 AKT phosphorylation generates 14-3-3 binding sites and regulates the nuclear/cytoplasmic distribution of DAF-16 |
| GO:0005634 nucleus | IDA PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: Key paper demonstrating DAF-16 nuclear accumulation in daf-2 mutants and after stress. Reason: Foundational evidence for nuclear localization of DAF-16. Supporting Evidence: PMID:11381260 Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei |
| GO:0005634 nucleus | IDA PMID:19454349 Conditioning protects C. elegans from lethal effects of ente... | ACCEPT | Summary: Nuclear localization demonstrated during pathogen conditioning response. Reason: Direct evidence of nuclear localization during immune activation. Supporting Evidence: PMID:19454349 the insulin/IGFR pathway, which regulates lifespan |
| GO:0005634 nucleus | IDA PMID:23911329 PQM-1 complements DAF-16 as a key transcriptional regulator ... | ACCEPT | Summary: Nuclear localization demonstrated in context of PQM-1 and DAF-16 interaction. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:23911329 PQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity. |
| GO:0005634 nucleus | IDA PMID:26154057 The Deubiquitylase MATH-33 Controls DAF-16 Stability and Fun... | ACCEPT | Summary: Nuclear localization demonstrated in context of MATH-33 deubiquitinase regulation of DAF-16. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:26154057 The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:11124266 Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA ... | ACCEPT | Summary: Direct demonstration of DAF-16 transcriptional activator activity using GAL4 fusion protein assays. Reason: Key evidence for DAF-16 as transcriptional activator. Supporting Evidence: PMID:11124266 In HepG2 cells, insulin signaling to PI 3-kinase/AKT inhibits the ability of a GAL4 DNA binding domain/DAF-16 fusion protein to activate transcription via the insulin-like growth factor binding protein-1-insulin response element, but not the GAL4 DNA binding site, which suggests that insulin inhibits the interaction of DAF-16 with its cognate DNA site |
| GO:0035556 intracellular signal transduction | IMP PMID:12750521 Regulation of aging and age-related disease by DAF-16 and he... | KEEP AS NON CORE | Summary: This annotation captures DAF-16's role in integrating stress signals and regulating downstream responses. Reason: While DAF-16 participates in signaling cascades, its primary function is as a transcription factor. Signal transduction is more of a pathway-level description than a core molecular function. Supporting Evidence: PMID:12750521 Regulation of aging and age-related disease by DAF-16 and heat-shock factor |
| GO:0008340 determination of adult lifespan | IMP PMID:11747825 daf-16 integrates developmental and environmental inputs to ... | ACCEPT | Summary: Foundational evidence that DAF-16 is required for lifespan extension. Reason: Core function of DAF-16. Loss of daf-16 suppresses longevity of daf-2 mutants. Supporting Evidence: PMID:11747825 nematodes carrying an integrated DAF-16::GFP transgene grow and reproduce more slowly yet are more stress resistant and longer lived than controls |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:26963674 A 44 bp intestine-specific hermaphrodite-specific enhancer f... | ACCEPT | Summary: DAF-16 represses vit-2 gene expression in intestine. Reason: DAF-16 can function as both activator and repressor. This documents its repressor function on specific genes. Supporting Evidence: PMID:26963674 2016 Mar 7. A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IGI PMID:26963674 A 44 bp intestine-specific hermaphrodite-specific enhancer f... | ACCEPT | Summary: Genetic interaction showing DAF-16 represses vit-2 with co-regulators. Reason: Supports DAF-16 role as transcriptional repressor on specific genes. Supporting Evidence: PMID:26963674 2016 Mar 7. A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:26963674 A 44 bp intestine-specific hermaphrodite-specific enhancer f... | ACCEPT | Summary: DAF-16 binds to vit-2 promoter regulatory region. Reason: Direct evidence of DNA binding to specific regulatory sequence. Supporting Evidence: PMID:26963674 2016 Mar 7. A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IMP PMID:26963674 A 44 bp intestine-specific hermaphrodite-specific enhancer f... | ACCEPT | Summary: DAF-16 functions as transcription factor regulating vit-2. Reason: Core molecular function demonstrated on specific target gene. Supporting Evidence: PMID:26963674 2016 Mar 7. A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. |
| GO:0005634 nucleus | IDA PMID:26963674 A 44 bp intestine-specific hermaphrodite-specific enhancer f... | ACCEPT | Summary: Nuclear localization demonstrated. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:26963674 2016 Mar 7. A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. |
| GO:0071889 14-3-3 protein binding | IPI PMID:17098225 The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis ... | ACCEPT | Summary: DAF-16 binds to 14-3-3 protein FTT-2, which sequesters DAF-16 in cytoplasm. This is a core regulatory mechanism. Reason: 14-3-3 binding is essential for DAF-16 regulation. FTT-2 binding to phosphorylated DAF-16 promotes cytoplasmic retention. Supporting Evidence: PMID:17098225 FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 by sequestering it in the cytoplasm |
| GO:0050829 defense response to Gram-negative bacterium | IGI PMID:16916933 Heat-shock transcription factor (HSF)-1 pathway required for... | ACCEPT | Summary: DAF-16 contributes to defense against Gram-negative bacteria, working with HSF-1. Reason: Innate immunity function is well-documented for DAF-16. Supporting Evidence: PMID:16916933 Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. |
| GO:0010468 regulation of gene expression | IMP PMID:32963007 Intergenerational pathogen-induced diapause in Caenorhabditi... | ACCEPT | Summary: DAF-16 regulates gene expression in intergenerational pathogen responses. Reason: General term consistent with DAF-16's transcription factor function. Supporting Evidence: PMID:32963007 Intergenerational Pathogen-Induced Diapause in Caenorhabditis elegans Is Modulated by mir-243. |
| GO:0030431 sleep | IGI PMID:29523076 Normal sleep bouts are not essential for C. elegans survival... | KEEP AS NON CORE | Summary: DAF-16 contributes to compensatory sleep changes in C. elegans. Reason: Sleep regulation is a secondary function of DAF-16, likely mediated through its stress response pathways. Not a core function. Supporting Evidence: PMID:29523076 Normal sleep bouts are not essential for C. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:25330323 The DAF-16 FOXO transcription factor regulates natc-1 to mod... | ACCEPT | Summary: DAF-16 represses natc-1 expression. Reason: Documents transcriptional repressor activity of DAF-16. Supporting Evidence: PMID:25330323 eCollection 2014 Oct. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:19506556 A soma-to-germline transformation in long-lived Caenorhabdit... | ACCEPT | Summary: DAF-16 binds to regulatory regions in chromatin. Reason: Direct evidence of sequence-specific DNA binding. Supporting Evidence: PMID:19506556 A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:19454349 Conditioning protects C. elegans from lethal effects of ente... | ACCEPT | Summary: DAF-16 is required for protection against EPEC following conditioning. Reason: Core innate immunity function documented with mutant phenotype. Supporting Evidence: PMID:19454349 Conditioning requires... the insulin/IGFR pathway, which regulates lifespan |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:23770237 Insulin/IGF-1 signaling regulates proteasome activity throug... | ACCEPT | Summary: DAF-16 represses ubh-4 deubiquitinase expression. Reason: Documents transcriptional repressor function on specific gene. Supporting Evidence: PMID:23770237 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IMP PMID:23770237 Insulin/IGF-1 signaling regulates proteasome activity throug... | ACCEPT | Summary: DAF-16 enhances proteasome activity by repressing ubh-4 and activating rpn-6.1. Reason: Well-documented function in proteostasis regulation. Supporting Evidence: PMID:22922647 increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16 PMID:23770237 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4. |
| GO:0010628 positive regulation of gene expression | IMP PMID:17526726 Specificity and complexity of the Caenorhabditis elegans inn... | ACCEPT | Summary: DAF-16 activates expression of immune response genes. Reason: Consistent with transcriptional activator function. Supporting Evidence: PMID:17526726 May 25. Specificity and complexity of the Caenorhabditis elegans innate immune response. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:24972867 Orthosiphon stamineus protects Caenorhabditis elegans agains... | ACCEPT | Summary: DAF-16 contributes to defense against Gram-positive S. aureus. Reason: Innate immunity function. Supporting Evidence: PMID:24972867 Orthosiphon stamineus protects Caenorhabditis elegans against Staphylococcus aureus infection through immunomodulation. |
| GO:1905909 regulation of dauer entry | IGI PMID:24671950 A Caenorhabditis elegans developmental decision requires ins... | ACCEPT | Summary: DAF-16 regulates dauer entry through neuron-intestine communication. Reason: Dauer regulation is a core function of DAF-16. Supporting Evidence: PMID:24671950 A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication. |
| GO:0008340 determination of adult lifespan | IMP PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media... | ACCEPT | Summary: DAF-16 affects lifespan in context of synaptic signaling. Reason: Core longevity function. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. |
| GO:0008582 regulation of synaptic assembly at neuromuscular junction | IGI PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media... | KEEP AS NON CORE | Summary: DAF-16 affects neuromuscular junction development. Reason: Secondary/pleiotropic function. NMJ regulation is not a core DAF-16 function. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. |
| GO:0045887 positive regulation of synaptic assembly at neuromuscular junction | IGI PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media... | KEEP AS NON CORE | Summary: DAF-16 promotes NMJ assembly in certain genetic contexts. Reason: Secondary/pleiotropic function. Not core to DAF-16 biology. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. |
| GO:1900075 positive regulation of neuromuscular synaptic transmission | IGI PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-media... | KEEP AS NON CORE | Summary: DAF-16 affects neuromuscular transmission. Reason: Secondary/pleiotropic function. Not core to DAF-16 biology. Supporting Evidence: PMID:23665919 Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. |
| GO:0010286 heat acclimation | IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: DAF-16 contributes to heat acclimation through PRMT-1 regulation. Reason: Heat stress response is a core DAF-16 function. Supporting Evidence: PMID:21531333 prmt-1 is also required for stress tolerance |
| GO:0071889 14-3-3 protein binding | IPI PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: DAF-16 interacts with 14-3-3 protein PAR-5/FTT-2. Reason: 14-3-3 binding is core regulatory mechanism. Supporting Evidence: PMID:21531333 prmt-1, the major asymmetric arginine methyltransferase, is a positive regulator of longevity in C. elegans |
| GO:0005634 nucleus | IDA PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: Nuclear localization demonstrated with PRMT-1 regulation. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:21531333 PRMT-1 methylates DAF-16, thereby blocking its phosphorylation by AKT |
| GO:0005737 cytoplasm | IDA PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: Cytoplasmic localization under normal conditions. Reason: Direct evidence of cytoplasmic localization. Supporting Evidence: PMID:21531333 prmt-1, the major asymmetric arginine methyltransferase, is a positive regulator of longevity in C. elegans |
| GO:0006979 response to oxidative stress | IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: DAF-16 mediates oxidative stress responses through PRMT-1. Reason: Oxidative stress response is core DAF-16 function. Supporting Evidence: PMID:21531333 prmt-1 is also required for stress tolerance |
| GO:0009411 response to UV | IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: DAF-16 contributes to UV stress response. Reason: UV response is part of DAF-16 stress response functions. Supporting Evidence: PMID:21531333 prmt-1 is also required for stress tolerance |
| GO:0010628 positive regulation of gene expression | IMP PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: DAF-16 activates longevity-related gene expression. Reason: Consistent with transcriptional activator function. Supporting Evidence: PMID:21531333 Disruption of PRMT-1 induces phosphorylation of DAF-16 with a concomitant reduction in the expression of longevity-related genes |
| GO:0010883 regulation of lipid storage | IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: DAF-16 regulates fat storage through PRMT-1 pathway. Reason: Lipid metabolism is a documented DAF-16 function. Supporting Evidence: PMID:21531333 prmt-1 is also required for stress tolerance and fat storage |
| GO:1905909 regulation of dauer entry | IGI PMID:21531333 Asymmetric arginine dimethylation determines life span in C.... | ACCEPT | Summary: DAF-16 regulates dauer formation. Reason: Dauer regulation is core DAF-16 function. Supporting Evidence: PMID:21531333 prmt-1 is also required for stress tolerance and fat storage but not dauer formation |
| GO:0008340 determination of adult lifespan | IMP PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorha... | ACCEPT | Summary: DAF-16 is required for lifespan extension by eIF4E reduction. Reason: Core longevity function. Supporting Evidence: PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. |
| GO:0008340 determination of adult lifespan | IGI PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorha... | ACCEPT | Summary: Genetic interaction with eIF4E for lifespan. Reason: Core longevity function. Supporting Evidence: PMID:17277769 eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. |
| GO:0008340 determination of adult lifespan | IGI PMID:27001890 Mondo complexes regulate TFEB via TOR inhibition to promote ... | ACCEPT | Summary: DAF-16 contributes to longevity in response to gonadal signals. Reason: Core longevity function. Supporting Evidence: PMID:27001890 Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals. |
| GO:0005634 nucleus | IDA PMID:24957743 The zinc matrix metalloproteinase ZMP-2 increases survival o... | ACCEPT | Summary: Nuclear localization in ZMP-2 study. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:24957743 The zinc matrix metalloproteinase ZMP-2 increases survival of Caenorhabditis elegans through interference with lipoprotein absorption. |
| GO:0005737 cytoplasm | IDA PMID:24957743 The zinc matrix metalloproteinase ZMP-2 increases survival o... | ACCEPT | Summary: Cytoplasmic localization in ZMP-2 study. Reason: Direct evidence of cytoplasmic localization. Supporting Evidence: PMID:24957743 The zinc matrix metalloproteinase ZMP-2 increases survival of Caenorhabditis elegans through interference with lipoprotein absorption. |
| GO:0008340 determination of adult lifespan | IMP PMID:27564576 Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is... | ACCEPT | Summary: DAF-16 affects lifespan in CNNM pathway study. Reason: Core longevity function. Supporting Evidence: PMID:27564576 eCollection 2016 Aug. |
| GO:0017151 DEAD/H-box RNA helicase binding | IPI PMID:26195740 RNA helicase HEL-1 promotes longevity by specifically activa... | ACCEPT | Summary: DAF-16 interacts with RNA helicase HEL-1, which promotes its activity. Reason: Specific protein binding interaction documented by co-IP. Supporting Evidence: PMID:26195740 RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans. |
| GO:0019899 enzyme binding | IPI PMID:23028355 C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocaliz... | ACCEPT | Summary: DAF-16 interacts with SIR-2.4 sirtuin enzyme. Reason: Documented protein interaction with enzymatic regulator. Supporting Evidence: PMID:23028355 2012 Sep 13. C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. |
| GO:0061065 regulation of dauer larval development | IGI PMID:21124868 Localization of a guanylyl cyclase to chemosensory cilia req... | ACCEPT | Summary: DAF-16 regulates dauer development in context of DAF-25. Reason: Dauer regulation is core DAF-16 function. Supporting Evidence: PMID:21124868 Localization of a guanylyl cyclase to chemosensory cilia requires the novel ciliary MYND domain protein DAF-25. |
| GO:0061065 regulation of dauer larval development | IGI PMID:1732156 Genetic analysis of chemosensory control of dauer formation ... | ACCEPT | Summary: Original genetic evidence placing daf-16 in dauer pathway. Reason: Foundational evidence for dauer regulation function. Supporting Evidence: PMID:1732156 Three genes, daf-16, daf-18 and daf-20, may affect downstream steps in a branched part of the pathway |
| GO:0007614 short-term memory | IGI PMID:26675724 The C. elegans adult neuronal IIS/FOXO transcriptome reveals... | KEEP AS NON CORE | Summary: DAF-16 contributes to associative memory in neurons. Reason: Memory function is a secondary/pleiotropic effect. Not a core function but documented. Supporting Evidence: PMID:26675724 The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators. |
| GO:0008340 determination of adult lifespan | IMP PMID:23352664 A fasting-responsive signaling pathway that extends life spa... | ACCEPT | Summary: DAF-16 mediates lifespan extension by fasting signaling. Reason: Core longevity function. Supporting Evidence: PMID:23352664 Jan 24. A fasting-responsive signaling pathway that extends life span in C. |
| GO:0008340 determination of adult lifespan | IGI PMID:23352664 A fasting-responsive signaling pathway that extends life spa... | ACCEPT | Summary: Genetic interaction for lifespan with fasting pathway. Reason: Core longevity function. Supporting Evidence: PMID:23352664 Jan 24. A fasting-responsive signaling pathway that extends life span in C. |
| GO:0042594 response to starvation | IMP PMID:23352664 A fasting-responsive signaling pathway that extends life spa... | ACCEPT | Summary: DAF-16 mediates fasting/starvation responses. Reason: Starvation response is core DAF-16 function. Supporting Evidence: PMID:23352664 Jan 24. A fasting-responsive signaling pathway that extends life span in C. |
| GO:1900426 positive regulation of defense response to bacterium | IMP PMID:22554143 An age-dependent reversal in the protective capacities of JN... | ACCEPT | Summary: DAF-16 promotes antibacterial defense with JNK signaling. Reason: Innate immunity is core DAF-16 function. Supporting Evidence: PMID:22554143 2012 May 30. An age-dependent reversal in the protective capacities of JNK signaling shortens Caenorhabditis elegans lifespan. |
| GO:0008013 beta-catenin binding | IPI PMID:15905404 Functional interaction between beta-catenin and FOXO in oxid... | ACCEPT | Summary: DAF-16 binds to beta-catenin BAR-1, which enhances its transcriptional activity during oxidative stress. Reason: Specific protein binding documented that is functionally important for oxidative stress response. Supporting Evidence: PMID:15905404 beta-Catenin binds directly to FOXO and enhances FOXO transcriptional activity |
| GO:0008340 determination of adult lifespan | IMP PMID:15905404 Functional interaction between beta-catenin and FOXO in oxid... | ACCEPT | Summary: BAR-1/beta-catenin affects DAF-16-dependent lifespan. Reason: Core longevity function. Supporting Evidence: PMID:15905404 loss of the beta-catenin BAR-1 reduces the activity of the FOXO ortholog DAF-16 in dauer formation and life span |
| GO:0034599 cellular response to oxidative stress | IGI PMID:15905404 Functional interaction between beta-catenin and FOXO in oxid... | ACCEPT | Summary: DAF-16 with BAR-1 mediates oxidative stress response. Reason: Oxidative stress response is core DAF-16 function. Supporting Evidence: PMID:15905404 BAR-1 was required for the oxidative stress-induced expression of the DAF-16 target gene sod-3 |
| GO:0040024 dauer larval development | IGI PMID:15905404 Functional interaction between beta-catenin and FOXO in oxid... | ACCEPT | Summary: DAF-16 with BAR-1 regulates dauer development. Reason: Dauer regulation is core DAF-16 function. Supporting Evidence: PMID:15905404 loss of the beta-catenin BAR-1 reduces the activity of the FOXO ortholog DAF-16 in dauer formation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:15905404 Functional interaction between beta-catenin and FOXO in oxid... | ACCEPT | Summary: DAF-16 activates transcription with BAR-1 enhancement. Reason: Core transcriptional activator function. Supporting Evidence: PMID:15905404 beta-Catenin binds directly to FOXO and enhances FOXO transcriptional activity |
| GO:1990381 ubiquitin-specific protease binding | IPI PMID:26154057 The Deubiquitylase MATH-33 Controls DAF-16 Stability and Fun... | ACCEPT | Summary: DAF-16 binds to MATH-33 deubiquitinase, which stabilizes it. Reason: Specific protein binding with regulatory importance. Supporting Evidence: PMID:26154057 The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity. |
| GO:0061066 positive regulation of dauer larval development | IMP PMID:6583682 A pheromone-induced developmental switch in Caenorhabditis e... | ACCEPT | Summary: DAF-16 promotes dauer formation; daf-16 mutants are dauer-defective. Reason: Core function in dauer development pathway. Supporting Evidence: PMID:6583682 A pheromone-induced developmental switch in Caenorhabditis elegans: Temperature-sensitive mutants reveal a wild-type temperature-dependent process. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stre... | ACCEPT | Summary: DAF-16 acts as transcription factor to activate rpn-6.1 expression. Reason: Core molecular function. Supporting Evidence: PMID:22922647 increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16 |
| GO:0006974 DNA damage response | IDA PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stre... | KEEP AS NON CORE | Summary: DAF-16 contributes to proteotoxic stress response including DNA damage. Reason: DNA damage response is secondary to the primary proteostasis function documented in this paper. The annotation may be over-interpreted from the proteotoxicity context. Supporting Evidence: PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stress conditions |
| GO:0005515 protein binding | IPI PMID:23255046 NSBP-1 mediates the effects of cholesterol on insulin/IGF-1 ... | MODIFY | Summary: DAF-16 interacts with NSBP-1 (nucleosome binding protein). Reason: "Protein binding" is too generic. Should be more specific if possible. Proposed replacements: protein-containing complex binding Supporting Evidence: PMID:23255046 Epub 2012 Dec 20. NSBP-1 mediates the effects of cholesterol on insulin/IGF-1 signaling in Caenorhabditis elegans. |
| GO:0005634 nucleus | IDA PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stre... | ACCEPT | Summary: Nuclear localization in proteotoxic stress study. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stress conditions |
| GO:0005829 cytosol | IDA PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stre... | ACCEPT | Summary: Cytosolic localization (more specific than cytoplasm). Reason: Direct evidence of cytosolic localization. Supporting Evidence: PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stress conditions |
| GO:0008340 determination of adult lifespan | IDA PMID:22922647 RPN-6 determines C. elegans longevity under proteotoxic stre... | ACCEPT | Summary: DAF-16 directly regulates longevity genes including rpn-6.1. Reason: Core longevity function demonstrated by direct assay. Supporting Evidence: PMID:22922647 increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16 |
| GO:0008340 determination of adult lifespan | IMP PMID:22560223 TOR signaling and rapamycin influence longevity by regulatin... | ACCEPT | Summary: DAF-16 required for lifespan effects of TOR signaling. Reason: Core longevity function. Supporting Evidence: PMID:22560223 TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. |
| GO:0040015 negative regulation of multicellular organism growth | IMP PMID:12571101 Cyclic GMP-dependent protein kinase EGL-4 controls body size... | ACCEPT | Summary: DAF-16 contributes to growth regulation with EGL-4/cGMP-dependent kinase. Reason: Growth regulation is documented DAF-16 function. Supporting Evidence: PMID:12571101 Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C elegans. |
| GO:0008340 determination of adult lifespan | IGI PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans... | ACCEPT | Summary: DAF-16 genetic interaction with RAGA-1 for lifespan. Reason: Core longevity function. Supporting Evidence: PMID:20523893 Manipulation of behavioral decline in Caenorhabditis elegans with the Rag GTPase raga-1. |
| GO:0045087 innate immune response | IMP PMID:19454349 Conditioning protects C. elegans from lethal effects of ente... | ACCEPT | Summary: DAF-16 required for innate immunity during EPEC conditioning. Reason: Core innate immunity function demonstrated with mutant phenotype. Supporting Evidence: PMID:19454349 Conditioning requires... the insulin/IGFR pathway, which regulates lifespan |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:19454349 Conditioning protects C. elegans from lethal effects of ente... | ACCEPT | Summary: DAF-16 activates transcription of immune genes during conditioning. Reason: Core transcriptional activator function. Supporting Evidence: PMID:19454349 Conditioning protects C. elegans from lethal effects of enteropathogenic E. coli by activating genes |
| GO:0140297 DNA-binding transcription factor binding | IPI PMID:19103192 Combined informatic and expression screen identifies the nov... | ACCEPT | Summary: DAF-16 interacts with HLH-13 transcription factor. Reason: Documented interaction between transcription factors. Supporting Evidence: PMID:19103192 2008 Dec 7. Combined informatic and expression screen identifies the novel DAF-16 target HLH-13. |
| GO:0005634 nucleus | IDA PMID:19252938 Feeding a ROS-generator to Caenorhabditis elegans leads to i... | ACCEPT | Summary: Nuclear localization demonstrated with ROS-generator treatment. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:19252938 Feeding a ROS-generator to Caenorhabditis elegans leads to increased expression of small heat shock protein HSP-16.2 and hormesis. |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:17894411 The MAP kinase JNK-1 of Caenorhabditis elegans: location, ac... | ACCEPT | Summary: DAF-16 regulates transcription with JNK-1 input. Reason: Core transcription regulation function. Supporting Evidence: PMID:17894411 The MAP kinase JNK-1 of Caenorhabditis elegans: location, activation, and influences over temperature-dependent insulin-like signaling, stress responses, and fitness. |
| GO:0002821 positive regulation of adaptive immune response | IMP PMID:18245330 DAF-16-dependent suppression of immunity during reproduction... | MODIFY | Summary: DAF-16 suppresses immunity during reproduction. Reason: C. elegans does not have adaptive immunity. This term is inappropriate for a nematode. Should use innate immunity term. Proposed replacements: innate immune response Supporting Evidence: PMID:18245330 Feb 1. DAF-16-dependent suppression of immunity during reproduction in Caenorhabditis elegans. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:17934462 DAF-16/FOXO targets genes that regulate tumor growth in Caen... | ACCEPT | Summary: DAF-16 promotes apoptosis in germline tumor model. Reason: Documented effect on apoptosis in tumor context. Supporting Evidence: PMID:17934462 DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans |
| GO:0046890 regulation of lipid biosynthetic process | IMP PMID:18762027 A 13C isotope labeling strategy reveals the influence of ins... | ACCEPT | Summary: DAF-16 regulates lipogenesis downstream of IIS. Reason: Lipid metabolism is documented DAF-16 function. Supporting Evidence: PMID:18762027 A 13C isotope labeling strategy reveals the influence of insulin signaling on lipogenesis in C. |
| GO:0060537 muscle tissue development | IMP PMID:18397876 Sirtuin inhibition protects from the polyalanine muscular dy... | KEEP AS NON CORE | Summary: DAF-16 affects muscle in polyalanine muscular dystrophy model. Reason: Muscle function is secondary/pleiotropic. DAF-16 is not a muscle-specific regulator. Supporting Evidence: PMID:18397876 Apr 7. Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1. |
| GO:0002119 nematode larval development | IMP PMID:11747821 Regulation of C. elegans DAF-16 and its human ortholog FKHRL... | ACCEPT | Summary: DAF-16 affects larval development and dauer decision. Reason: Developmental regulation is core DAF-16 function. Supporting Evidence: PMID:11747821 C. elegans insulin-like signaling regulates metabolism, development, and life span |
| GO:0002821 positive regulation of adaptive immune response | IMP PMID:17096597 p38 MAPK regulates expression of immune response genes and c... | MODIFY | Summary: DAF-16 contributes to immune response. Reason: C. elegans does not have adaptive immunity. Should use innate immunity. Proposed replacements: innate immune response Supporting Evidence: PMID:17096597 p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans |
| GO:0005634 nucleus | IDA PMID:11747821 Regulation of C. elegans DAF-16 and its human ortholog FKHRL... | ACCEPT | Summary: Nuclear localization demonstrated with GFP fusion. Reason: Direct evidence of nuclear localization. Supporting Evidence: PMID:11747821 daf-2 insulin signaling, via AKT kinases, negatively regulates DAF-16 by controlling its nuclear localization |
| GO:0005737 cytoplasm | IDA PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: Cytoplasmic localization under fed conditions. Reason: Direct evidence of cytoplasmic localization. Supporting Evidence: PMID:11381260 Here, we show that the DAF-2 pathway prevents DAF-16 accumulation in nuclei |
| GO:0005737 cytoplasm | IDA PMID:11747821 Regulation of C. elegans DAF-16 and its human ortholog FKHRL... | ACCEPT | Summary: Cytoplasmic localization with DAF-2 signaling. Reason: Direct evidence of cytoplasmic localization. Supporting Evidence: PMID:11747821 daf-2 insulin signaling, via AKT kinases, negatively regulates DAF-16 by controlling its nuclear localization |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:17096597 p38 MAPK regulates expression of immune response genes and c... | ACCEPT | Summary: DAF-16 regulates transcription of immune genes. Reason: Core transcription regulation function. Supporting Evidence: PMID:17096597 p38 MAPK regulates expression of immune response genes |
| GO:0008286 insulin receptor signaling pathway | TAS PMID:11747821 Regulation of C. elegans DAF-16 and its human ortholog FKHRL... | ACCEPT | Summary: DAF-16 is major output of insulin receptor signaling in C. elegans. Reason: Core pathway annotation well-supported by literature. Supporting Evidence: PMID:11747821 C. elegans insulin-like signaling regulates metabolism, development, and life span |
| GO:0008340 determination of adult lifespan | IMP PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: daf-16 mutants suppress lifespan extension of daf-2 mutants. Reason: Foundational evidence for DAF-16 longevity function. Supporting Evidence: PMID:11381260 This lifespan extension requires DAF-16 |
| GO:0008340 determination of adult lifespan | IMP PMID:11747821 Regulation of C. elegans DAF-16 and its human ortholog FKHRL... | ACCEPT | Summary: DAF-16 required for lifespan extension. Reason: Core longevity function. Supporting Evidence: PMID:11747821 C. elegans insulin-like signaling regulates metabolism, development, and life span |
| GO:0009411 response to UV | IDA PMID:11747825 daf-16 integrates developmental and environmental inputs to ... | ACCEPT | Summary: DAF-16 responds to UV stress. Reason: UV stress response is part of general stress response function. Supporting Evidence: PMID:11747825 Environmental stresses, such as starvation, heat, and oxidative stress, cause rapid nuclear localization of DAF-16 |
| GO:0010564 regulation of cell cycle process | IEP PMID:17934462 DAF-16/FOXO targets genes that regulate tumor growth in Caen... | KEEP AS NON CORE | Summary: DAF-16 affects cell cycle in germline tumor model. Reason: Cell cycle regulation is secondary to tumor suppressor function. IEP evidence is weaker. Supporting Evidence: PMID:17934462 DAF-16/FOXO targets genes that regulate tumor growth |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:17276341 RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by... | ACCEPT | Summary: DAF-16 interacts with RLE-1 E3 ubiquitin ligase that ubiquitinates it. Reason: Specific protein binding with regulatory importance for DAF-16 turnover. Supporting Evidence: PMID:17276341 RLE-1, an E3 ubiquitin ligase, regulates C. |
| GO:0034605 cellular response to heat | IDA PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: Heat stress causes DAF-16 nuclear accumulation. Reason: Heat stress response is core DAF-16 function. Supporting Evidence: PMID:11381260 We find that both sensory neurons and germline activity regulate DAF-16 accumulation in nuclei |
| GO:0034605 cellular response to heat | IDA PMID:11747825 daf-16 integrates developmental and environmental inputs to ... | ACCEPT | Summary: Heat stress induces DAF-16 nuclear translocation. Reason: Core stress response function. Supporting Evidence: PMID:11747825 Environmental stresses, such as starvation, heat, and oxidative stress, cause rapid nuclear localization of DAF-16 |
| GO:0005515 protein binding | IPI PMID:11124266 Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA ... | MODIFY | Summary: DAF-16 interacts with 14-3-3 proteins. Reason: "Protein binding" is too generic. This is 14-3-3 binding specifically. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:11124266 AKT phosphorylation generates 14-3-3 binding sites and regulates the nuclear/cytoplasmic distribution of DAF-16 |
| GO:0008286 insulin receptor signaling pathway | IDA PMID:11124266 Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA ... | ACCEPT | Summary: DAF-16 is directly phosphorylated by AKT downstream of insulin signaling. Reason: Core pathway annotation. Direct biochemical evidence. Supporting Evidence: PMID:11124266 C. elegans DAF-16 is a direct target of AKT |
| GO:0008340 determination of adult lifespan | IGI PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: Genetic interaction with daf-2 for lifespan. Reason: Core longevity function. Supporting Evidence: PMID:11381260 This lifespan extension requires DAF-16 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:11124266 Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA ... | ACCEPT | Summary: DAF-16 activates transcription through DNA binding. Reason: Core transcriptional activator function demonstrated directly. Supporting Evidence: PMID:11124266 a GAL4 DNA binding domain/DAF-16 fusion protein to activate transcription |
| GO:0040024 dauer larval development | IGI PMID:11381260 Regulation of the Caenorhabditis elegans longevity protein D... | ACCEPT | Summary: DAF-16 regulates dauer formation. Reason: Core developmental function. Supporting Evidence: PMID:11381260 Together these findings reveal unexpected complexity in the DAF-16-dependent pathways that regulate aging |
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Download this section (compressed HTML)Q: What are the distinct functions of DAF-16 isoforms (a, d/f) in different tissues?
Q: How does DAF-16 coordinate transcriptional activation and repression?
Experiment: ChIP-seq across conditions and tissues to identify isoform-specific target genes
Hypothesis: Comprehensive genome-wide binding analysis would reveal the full scope of DAF-16 targets and potential isoform-specific binding patterns.
Experiment: Single-cell analysis of DAF-16 nuclear translocation dynamics
Hypothesis: Cell-type-specific dynamics of DAF-16 regulation could reveal tissue-specific mechanisms of DAF-16 activation.
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