id: O16850
gene_symbol: daf-16
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: '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.

  '
existing_annotations:
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.

      '
    action: ACCEPT
    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].

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: 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
    - reference_id: file:worm/daf-16/daf-16-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.

      '
    action: ACCEPT
    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].

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: Here, we show that the DAF-2 pathway prevents DAF-16 
        accumulation in nuclei
    - reference_id: PMID:11747825
      supporting_text: Environmental stresses, such as starvation, heat, and 
        oxidative stress, cause rapid nuclear localization of DAF-16
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.

      '
    action: ACCEPT
    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].

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: increased expression of rpn-6, a subunit of the 19S 
        proteasome, by the FOXO transcription factor DAF-16
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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]

      '
    action: ACCEPT
    reason: 'Sequence-specific DNA binding is central to DAF-16 function. The forkhead
      domain mediates binding to DBE elements in target promoters [PMID:11124266].

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: 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
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase 
      II-specific
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.

      '
    action: ACCEPT
    reason: 'DAF-16 activates transcription of many longevity and stress response
      genes. The IEA annotation is consistent with experimental data [PMID:11124266,
      PMID:22922647].

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: 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
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: 'DAF-16 is involved in C. elegans innate immunity, regulating defense
      responses to bacterial pathogens. This annotation is supported by experimental
      evidence.

      '
    action: ACCEPT
    reason: 'DAF-16''s role in immunity is well-established. It regulates immune response
      genes and contributes to pathogen resistance [PMID:17096597, PMID:19454349].

      '
    supported_by:
    - reference_id: PMID:17096597
      supporting_text: p38 MAPK regulates expression of immune response genes 
        and contributes to longevity in C. elegans
    - reference_id: PMID:19454349
      supporting_text: Conditioning requires... the insulin/IGFR pathway, which 
        regulates lifespan
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.

      '
    action: ACCEPT
    reason: 'DNA binding is fundamental to DAF-16 function. The forkhead domain enables
      DNA binding, and this is consistent with more specific annotations.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: 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
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'DAF-16 is a DNA-binding transcription factor, a core function supported
      by InterPro domain annotation (forkhead domain).

      '
    action: ACCEPT
    reason: 'This is the fundamental molecular function of DAF-16. IEA from InterPro
      is consistent with experimental evidence.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: a GAL4 DNA binding domain/DAF-16 fusion protein to 
        activate transcription
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: 'Nuclear localization is essential for DAF-16 transcriptional activity.
      Duplicate of IBA annotation with same term.

      '
    action: ACCEPT
    reason: 'Consistent with IBA and experimental evidence. DAF-16 translocates to
      nucleus under stress and low IIS conditions [PMID:11381260].

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: Here, we show that the DAF-2 pathway prevents DAF-16 
        accumulation in nuclei
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: 'DAF-16 is retained in the cytoplasm when IIS is active, through phosphorylation
      and 14-3-3 protein binding.

      '
    action: ACCEPT
    reason: 'Cytoplasmic localization under fed/unstressed conditions is well-documented.
      AKT phosphorylation promotes 14-3-3 binding and cytoplasmic retention [PMID:11381260,
      PMID:17098225].

      '
    supported_by:
    - reference_id: PMID:17098225
      supporting_text: FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 
        by sequestering it in the cytoplasm
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: 'DAF-16 participates in DNA-templated transcription as a transcription
      factor. This is a parent term of more specific transcription regulation terms.

      '
    action: ACCEPT
    reason: 'Consistent with DAF-16''s role as a transcription factor regulating gene
      expression.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: a GAL4 DNA binding domain/DAF-16 fusion protein to 
        activate transcription
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'DAF-16 regulates transcription of target genes. This IEA from InterPro
      is consistent with its forkhead domain function.

      '
    action: ACCEPT
    reason: 'Core function of DAF-16. Regulates transcription of numerous target genes
      involved in longevity, stress response, and metabolism.

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: increased expression of rpn-6, a subunit of the 19S 
        proteasome, by the FOXO transcription factor DAF-16
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.

      '
    action: ACCEPT
    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].

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: The lifespan of Caenorhabditis elegans is regulated by 
        the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2
    - reference_id: PMID:11747821
      supporting_text: daf-2 insulin signaling, via AKT kinases, negatively 
        regulates DAF-16 by controlling its nuclear localization
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'DAF-16 is essential for lifespan extension in daf-2 mutants and other
      longevity paradigms. This is a core function of DAF-16.

      '
    action: ACCEPT
    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].

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: This lifespan extension requires DAF-16, a 
        forkhead/winged-helix transcription factor
- term:
    id: GO:0009896
    label: positive regulation of catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'DAF-16 regulates proteasome activity and protein catabolism. It activates
      rpn-6.1 expression to enhance proteasome function.

      '
    action: ACCEPT
    reason: 'DAF-16 promotes protein catabolism through upregulation of proteasome
      components. This is supported by experimental evidence [PMID:22922647, PMID:23770237].

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: increased expression of rpn-6, a subunit of the 19S 
        proteasome, by the FOXO transcription factor DAF-16
- term:
    id: GO:0010883
    label: regulation of lipid storage
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'DAF-16 regulates lipid metabolism and fat storage. daf-2 mutants accumulate
      fat in a DAF-16-dependent manner.

      '
    action: ACCEPT
    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].

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1 is also required for stress tolerance and fat 
        storage but not dauer formation in daf-2 mutants
- term:
    id: GO:0031349
    label: positive regulation of defense response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'DAF-16 positively regulates innate immune responses to pathogens.

      '
    action: ACCEPT
    reason: 'DAF-16 contributes to pathogen resistance and immune gene expression
      [PMID:17096597, PMID:19454349].

      '
    supported_by:
    - reference_id: PMID:19454349
      supporting_text: Conditioning requires... the insulin/IGFR pathway, which 
        regulates lifespan
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'DAF-16 mediates responses to oxidative stress, including activation
      of antioxidant genes like sod-3.

      '
    action: ACCEPT
    reason: 'Oxidative stress response is a core DAF-16 function. DAF-16 activates
      sod-3 and other stress response genes [PMID:15905404, PMID:11747825].

      '
    supported_by:
    - reference_id: PMID:15905404
      supporting_text: BAR-1 was required for the oxidative stress-induced 
        expression of the DAF-16 target gene sod-3
    - reference_id: PMID:11747825
      supporting_text: Environmental stresses, such as starvation, heat, and 
        oxidative stress, cause rapid nuclear localization of DAF-16
- term:
    id: GO:0040015
    label: negative regulation of multicellular organism growth
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'Activation of DAF-16 leads to reduced growth and reproduction, as resources
      are diverted to stress resistance.

      '
    action: ACCEPT
    reason: 'DAF-16 activation causes growth trade-offs. DAF-16::GFP transgenic animals
      grow more slowly but are stress resistant [PMID:11747825].

      '
    supported_by:
    - reference_id: PMID:11747825
      supporting_text: nematodes carrying an integrated DAF-16::GFP transgene 
        grow and reproduce more slowly yet are more stress resistant and longer 
        lived
- term:
    id: GO:0042594
    label: response to starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'DAF-16 is activated by starvation and mediates starvation responses.

      '
    action: ACCEPT
    reason: 'Starvation induces DAF-16 nuclear localization and activation of survival
      programs [PMID:11747825, PMID:11381260].

      '
    supported_by:
    - reference_id: PMID:11747825
      supporting_text: Environmental stresses, such as starvation, heat, and 
        oxidative stress, cause rapid nuclear localization of DAF-16
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'DAF-16 binds to specific DNA sequences (DBE: TTGTTTAC) in target promoters.

      '
    action: ACCEPT
    reason: 'Sequence-specific binding via forkhead domain is core to DAF-16 function.
      InterPro annotation consistent with experimental data.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: 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
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: 'DAF-16 regulates innate immunity in C. elegans, contributing to pathogen
      resistance.

      '
    action: ACCEPT
    reason: 'Innate immune function is well-documented for DAF-16 [PMID:17096597,
      PMID:19454349].

      '
    supported_by:
    - reference_id: PMID:17096597
      supporting_text: p38 MAPK regulates expression of immune response genes 
        and contributes to longevity in C. elegans
- term:
    id: GO:0050778
    label: positive regulation of immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'DAF-16 positively regulates immune response gene expression.

      '
    action: ACCEPT
    reason: 'Consistent with DAF-16''s role in innate immunity and defense responses
      [PMID:17096597, PMID:19454349].

      '
    supported_by:
    - reference_id: PMID:19454349
      supporting_text: Conditioning requires... the insulin/IGFR pathway, which 
        regulates lifespan
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15068796
  review:
    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.

      '
    action: MODIFY
    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_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
    supported_by:
    - reference_id: PMID:15068796
      supporting_text: SGK-1 forms a protein complex with the AKT kinases... All
        three kinases of this complex are able to directly phosphorylate 
        DAF-16/FKHRL1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16777605
  review:
    summary: 'This annotation documents DAF-16 interaction with SIR-2.1 sirtuin, which
      promotes DAF-16 activity during stress.

      '
    action: MODIFY
    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_replacement_terms:
    - id: GO:0042826
      label: histone deacetylase binding
    supported_by:
    - reference_id: PMID:16777605
      supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
        14-3-3-dependent manner
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16860373
  review:
    summary: 'This annotation documents DAF-16 interaction with SIR-2.1 and 14-3-3
      proteins.

      '
    action: MODIFY
    reason: '"Protein binding" is too generic. This represents 14-3-3 binding (GO:0071889)
      which is already annotated more specifically elsewhere.

      '
    proposed_replacement_terms:
    - id: GO:0071889
      label: 14-3-3 protein binding
    supported_by:
    - reference_id: PMID:16860373
      supporting_text: C. elegans 14-3-3 proteins regulate life span and 
        interact with SIR-2.1 and DAF-16/FOXO
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18358814
  review:
    summary: 'This annotation documents DAF-16 interaction with AKT-1, AKT-2, and
      SGK-1. Duplicate of PMID:15068796 annotation.

      '
    action: MODIFY
    reason: '"Protein binding" is too generic. These are regulatory kinase interactions.

      '
    proposed_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
    supported_by:
    - reference_id: PMID:18358814
      supporting_text: The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:16777605
  review:
    summary: 'Nuclear localization documented in context of SIR-2.1/14-3-3 regulation.

      '
    action: ACCEPT
    reason: 'Consistent with numerous other annotations for nuclear localization.

      '
    supported_by:
    - reference_id: PMID:16777605
      supporting_text: 14-3-3 proteins are also required for SIR-2.1-induced 
        transcriptional activation of DAF-16
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:16777605
  review:
    summary: 'Cytoplasmic localization documented in context of 14-3-3 sequestration.

      '
    action: ACCEPT
    reason: 'Consistent with DAF-16 nucleocytoplasmic shuttling behavior.

      '
    supported_by:
    - reference_id: PMID:16777605
      supporting_text: 14-3-3 genes are required for the life-span extension 
        conferred by extra copies of sir-2.1
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:17098225
  review:
    summary: 'FTT-2 sequesters DAF-16 in the cytoplasm under normal conditions.

      '
    action: ACCEPT
    reason: 'Cytoplasmic retention by FTT-2/14-3-3 is well-documented mechanism of
      DAF-16 regulation.

      '
    supported_by:
    - reference_id: PMID:17098225
      supporting_text: FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 
        by sequestering it in the cytoplasm
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: NAS
  original_reference_id: PMID:16777605
  review:
    summary: 'DAF-16 activates transcription of target genes. SIR-2.1 and 14-3-3 enhance
      this activation.

      '
    action: ACCEPT
    reason: 'Consistent with DAF-16''s role as a transcriptional activator.

      '
    supported_by:
    - reference_id: PMID:16777605
      supporting_text: 14-3-3 proteins are also required for SIR-2.1-induced 
        transcriptional activation of DAF-16
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: NAS
  original_reference_id: PMID:16777605
  review:
    summary: 'DAF-16 also represses some target genes.

      '
    action: ACCEPT
    reason: 'DAF-16 functions as both activator and repressor depending on target
      gene.

      '
    supported_by:
    - reference_id: PMID:16777605
      supporting_text: 14-3-3 proteins are also required for SIR-2.1-induced 
        transcriptional activation of DAF-16
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: NAS
  original_reference_id: PMID:17098225
  review:
    summary: 'DAF-16 represses some target genes including ins-7 and others.

      '
    action: ACCEPT
    reason: 'DAF-16 can repress gene expression in addition to activating genes.

      '
    supported_by:
    - reference_id: PMID:17098225
      supporting_text: ftt-2 knock down caused the nuclear accumulation of 
        DAF-16/FOXO... and enhanced the transcriptional activities of DAF-16
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: NAS
  original_reference_id: PMID:16777605
  review:
    summary: 'DAF-16 mediates heat stress responses. Heat stress promotes SIR-2.1/DAF-16
      interaction.

      '
    action: ACCEPT
    reason: 'Heat stress response is a well-documented DAF-16 function [PMID:11381260,
      PMID:11747825].

      '
    supported_by:
    - reference_id: PMID:16777605
      supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
        14-3-3-dependent manner
- term:
    id: GO:0051457
    label: maintenance of protein location in nucleus
  evidence_type: NAS
  original_reference_id: PMID:16777605
  review:
    summary: 'This annotation appears to describe nuclear retention of DAF-16 following
      stress-induced nuclear translocation.

      '
    action: KEEP_AS_NON_CORE
    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.

      '
    supported_by:
    - reference_id: PMID:16777605
      supporting_text: Following heat stress, SIR-2.1 can bind DAF-16 in a 
        14-3-3-dependent manner
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:11124266
  review:
    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.

      '
    action: ACCEPT
    reason: 'Core molecular function demonstrated by direct assay. DAF-16 binds to
      the insulin response element [PMID:11124266].

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: 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
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19506556
  review:
    summary: 'ChIP experiments demonstrating DAF-16 binding to chromatin in germline-less
      long-lived mutants.

      '
    action: ACCEPT
    reason: 'Direct evidence of DAF-16 DNA binding by ChIP analysis.

      '
    supported_by:
    - reference_id: PMID:19506556
      supporting_text: A soma-to-germline transformation in long-lived 
        Caenorhabditis elegans mutants
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11124266
  review:
    summary: 'Nuclear localization demonstrated in this foundational paper on DAF-16
      regulation.

      '
    action: ACCEPT
    reason: 'Direct experimental evidence of nuclear localization.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: AKT phosphorylation generates 14-3-3 binding sites and 
        regulates the nuclear/cytoplasmic distribution of DAF-16
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11381260
  review:
    summary: 'Key paper demonstrating DAF-16 nuclear accumulation in daf-2 mutants
      and after stress.

      '
    action: ACCEPT
    reason: 'Foundational evidence for nuclear localization of DAF-16.

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: Here, we show that the DAF-2 pathway prevents DAF-16 
        accumulation in nuclei
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:19454349
  review:
    summary: 'Nuclear localization demonstrated during pathogen conditioning response.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization during immune activation.

      '
    supported_by:
    - reference_id: PMID:19454349
      supporting_text: the insulin/IGFR pathway, which regulates lifespan
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23911329
  review:
    summary: 'Nuclear localization demonstrated in context of PQM-1 and DAF-16 interaction.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    additional_reference_ids:
    - PMID:23911329
    supported_by:
    - reference_id: PMID:23911329
      supporting_text: PQM-1 complements DAF-16 as a key transcriptional 
        regulator of DAF-2-mediated development and longevity.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:26154057
  review:
    summary: 'Nuclear localization demonstrated in context of MATH-33 deubiquitinase
      regulation of DAF-16.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    additional_reference_ids:
    - PMID:26154057
    supported_by:
    - reference_id: PMID:26154057
      supporting_text: The Deubiquitylase MATH-33 Controls DAF-16 Stability and 
        Function in Metabolism and Longevity.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase 
      II-specific
  evidence_type: IDA
  original_reference_id: PMID:11124266
  review:
    summary: 'Direct demonstration of DAF-16 transcriptional activator activity using
      GAL4 fusion protein assays.

      '
    action: ACCEPT
    reason: 'Key evidence for DAF-16 as transcriptional activator.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: 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
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IMP
  original_reference_id: PMID:12750521
  review:
    summary: 'This annotation captures DAF-16''s role in integrating stress signals
      and regulating downstream responses.

      '
    action: KEEP_AS_NON_CORE
    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.

      '
    supported_by:
    - reference_id: PMID:12750521
      supporting_text: Regulation of aging and age-related disease by DAF-16 and
        heat-shock factor
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:11747825
  review:
    summary: 'Foundational evidence that DAF-16 is required for lifespan extension.

      '
    action: ACCEPT
    reason: 'Core function of DAF-16. Loss of daf-16 suppresses longevity of daf-2
      mutants.

      '
    supported_by:
    - reference_id: PMID:11747825
      supporting_text: nematodes carrying an integrated DAF-16::GFP transgene 
        grow and reproduce more slowly yet are more stress resistant and longer 
        lived than controls
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:26963674
  review:
    summary: 'DAF-16 represses vit-2 gene expression in intestine.

      '
    action: ACCEPT
    reason: 'DAF-16 can function as both activator and repressor. This documents its
      repressor function on specific genes.

      '
    additional_reference_ids:
    - PMID:26963674
    supported_by:
    - reference_id: PMID:26963674
      supporting_text: 2016 Mar 7. A 44 bp intestine-specific 
        hermaphrodite-specific enhancer from the C.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IGI
  original_reference_id: PMID:26963674
  review:
    summary: 'Genetic interaction showing DAF-16 represses vit-2 with co-regulators.

      '
    action: ACCEPT
    reason: 'Supports DAF-16 role as transcriptional repressor on specific genes.

      '
    additional_reference_ids:
    - PMID:26963674
    supported_by:
    - reference_id: PMID:26963674
      supporting_text: 2016 Mar 7. A 44 bp intestine-specific 
        hermaphrodite-specific enhancer from the C.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:26963674
  review:
    summary: 'DAF-16 binds to vit-2 promoter regulatory region.

      '
    action: ACCEPT
    reason: 'Direct evidence of DNA binding to specific regulatory sequence.

      '
    additional_reference_ids:
    - PMID:26963674
    supported_by:
    - reference_id: PMID:26963674
      supporting_text: 2016 Mar 7. A 44 bp intestine-specific 
        hermaphrodite-specific enhancer from the C.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IMP
  original_reference_id: PMID:26963674
  review:
    summary: 'DAF-16 functions as transcription factor regulating vit-2.

      '
    action: ACCEPT
    reason: 'Core molecular function demonstrated on specific target gene.

      '
    additional_reference_ids:
    - PMID:26963674
    supported_by:
    - reference_id: PMID:26963674
      supporting_text: 2016 Mar 7. A 44 bp intestine-specific 
        hermaphrodite-specific enhancer from the C.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:26963674
  review:
    summary: 'Nuclear localization demonstrated.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    additional_reference_ids:
    - PMID:26963674
    supported_by:
    - reference_id: PMID:26963674
      supporting_text: 2016 Mar 7. A 44 bp intestine-specific 
        hermaphrodite-specific enhancer from the C.
- term:
    id: GO:0071889
    label: 14-3-3 protein binding
  evidence_type: IPI
  original_reference_id: PMID:17098225
  review:
    summary: 'DAF-16 binds to 14-3-3 protein FTT-2, which sequesters DAF-16 in cytoplasm.
      This is a core regulatory mechanism.

      '
    action: ACCEPT
    reason: '14-3-3 binding is essential for DAF-16 regulation. FTT-2 binding to phosphorylated
      DAF-16 promotes cytoplasmic retention.

      '
    supported_by:
    - reference_id: PMID:17098225
      supporting_text: FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 
        by sequestering it in the cytoplasm
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IGI
  original_reference_id: PMID:16916933
  review:
    summary: 'DAF-16 contributes to defense against Gram-negative bacteria, working
      with HSF-1.

      '
    action: ACCEPT
    reason: 'Innate immunity function is well-documented for DAF-16.

      '
    additional_reference_ids:
    - PMID:16916933
    supported_by:
    - reference_id: PMID:16916933
      supporting_text: Heat-shock transcription factor (HSF)-1 pathway required 
        for Caenorhabditis elegans immunity.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:32963007
  review:
    summary: 'DAF-16 regulates gene expression in intergenerational pathogen responses.

      '
    action: ACCEPT
    reason: 'General term consistent with DAF-16''s transcription factor function.

      '
    additional_reference_ids:
    - PMID:32963007
    supported_by:
    - reference_id: PMID:32963007
      supporting_text: Intergenerational Pathogen-Induced Diapause in 
        Caenorhabditis elegans Is Modulated by mir-243.
- term:
    id: GO:0030431
    label: sleep
  evidence_type: IGI
  original_reference_id: PMID:29523076
  review:
    summary: 'DAF-16 contributes to compensatory sleep changes in C. elegans.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Sleep regulation is a secondary function of DAF-16, likely mediated through
      its stress response pathways. Not a core function.

      '
    additional_reference_ids:
    - PMID:29523076
    supported_by:
    - reference_id: PMID:29523076
      supporting_text: Normal sleep bouts are not essential for C.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:25330323
  review:
    summary: 'DAF-16 represses natc-1 expression.

      '
    action: ACCEPT
    reason: 'Documents transcriptional repressor activity of DAF-16.

      '
    additional_reference_ids:
    - PMID:25330323
    supported_by:
    - reference_id: PMID:25330323
      supporting_text: eCollection 2014 Oct.
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific 
      DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19506556
  review:
    summary: 'DAF-16 binds to regulatory regions in chromatin.

      '
    action: ACCEPT
    reason: 'Direct evidence of sequence-specific DNA binding.

      '
    additional_reference_ids:
    - PMID:19506556
    supported_by:
    - reference_id: PMID:19506556
      supporting_text: A soma-to-germline transformation in long-lived 
        Caenorhabditis elegans mutants.
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IMP
  original_reference_id: PMID:19454349
  review:
    summary: 'DAF-16 is required for protection against EPEC following conditioning.

      '
    action: ACCEPT
    reason: 'Core innate immunity function documented with mutant phenotype.

      '
    supported_by:
    - reference_id: PMID:19454349
      supporting_text: Conditioning requires... the insulin/IGFR pathway, which 
        regulates lifespan
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:23770237
  review:
    summary: 'DAF-16 represses ubh-4 deubiquitinase expression.

      '
    action: ACCEPT
    reason: 'Documents transcriptional repressor function on specific gene.

      '
    additional_reference_ids:
    - PMID:23770237
    supported_by:
    - reference_id: PMID:23770237
      supporting_text: 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome
        activity through the deubiquitinating enzyme UBH-4.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein 
      catabolic process
  evidence_type: IMP
  original_reference_id: PMID:23770237
  review:
    summary: 'DAF-16 enhances proteasome activity by repressing ubh-4 and activating
      rpn-6.1.

      '
    action: ACCEPT
    reason: 'Well-documented function in proteostasis regulation.

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: increased expression of rpn-6, a subunit of the 19S 
        proteasome, by the FOXO transcription factor DAF-16
    - reference_id: PMID:23770237
      supporting_text: 2013 Jun 13. Insulin/IGF-1 signaling regulates proteasome
        activity through the deubiquitinating enzyme UBH-4.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:17526726
  review:
    summary: 'DAF-16 activates expression of immune response genes.

      '
    action: ACCEPT
    reason: 'Consistent with transcriptional activator function.

      '
    additional_reference_ids:
    - PMID:17526726
    supported_by:
    - reference_id: PMID:17526726
      supporting_text: May 25. Specificity and complexity of the Caenorhabditis 
        elegans innate immune response.
- term:
    id: GO:0050830
    label: defense response to Gram-positive bacterium
  evidence_type: IMP
  original_reference_id: PMID:24972867
  review:
    summary: 'DAF-16 contributes to defense against Gram-positive S. aureus.

      '
    action: ACCEPT
    reason: 'Innate immunity function.

      '
    additional_reference_ids:
    - PMID:24972867
    supported_by:
    - reference_id: PMID:24972867
      supporting_text: Orthosiphon stamineus protects Caenorhabditis elegans 
        against Staphylococcus aureus infection through immunomodulation.
- term:
    id: GO:1905909
    label: regulation of dauer entry
  evidence_type: IGI
  original_reference_id: PMID:24671950
  review:
    summary: 'DAF-16 regulates dauer entry through neuron-intestine communication.

      '
    action: ACCEPT
    reason: 'Dauer regulation is a core function of DAF-16.

      '
    additional_reference_ids:
    - PMID:24671950
    supported_by:
    - reference_id: PMID:24671950
      supporting_text: A Caenorhabditis elegans developmental decision requires 
        insulin signaling-mediated neuron-intestine communication.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:23665919
  review:
    summary: 'DAF-16 affects lifespan in context of synaptic signaling.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:23665919
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:0008582
    label: regulation of synaptic assembly at neuromuscular junction
  evidence_type: IGI
  original_reference_id: PMID:23665919
  review:
    summary: 'DAF-16 affects neuromuscular junction development.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Secondary/pleiotropic function. NMJ regulation is not a core DAF-16 function.

      '
    additional_reference_ids:
    - PMID:23665919
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:0045887
    label: positive regulation of synaptic assembly at neuromuscular junction
  evidence_type: IGI
  original_reference_id: PMID:23665919
  review:
    summary: 'DAF-16 promotes NMJ assembly in certain genetic contexts.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Secondary/pleiotropic function. Not core to DAF-16 biology.

      '
    additional_reference_ids:
    - PMID:23665919
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:1900075
    label: positive regulation of neuromuscular synaptic transmission
  evidence_type: IGI
  original_reference_id: PMID:23665919
  review:
    summary: 'DAF-16 affects neuromuscular transmission.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Secondary/pleiotropic function. Not core to DAF-16 biology.

      '
    additional_reference_ids:
    - PMID:23665919
    supported_by:
    - reference_id: PMID:23665919
      supporting_text: Attenuation of insulin signalling contributes to 
        FSN-1-mediated regulation of synapse development.
- term:
    id: GO:0010286
    label: heat acclimation
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: 'DAF-16 contributes to heat acclimation through PRMT-1 regulation.

      '
    action: ACCEPT
    reason: 'Heat stress response is a core DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1 is also required for stress tolerance
- term:
    id: GO:0071889
    label: 14-3-3 protein binding
  evidence_type: IPI
  original_reference_id: PMID:21531333
  review:
    summary: 'DAF-16 interacts with 14-3-3 protein PAR-5/FTT-2.

      '
    action: ACCEPT
    reason: '14-3-3 binding is core regulatory mechanism.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1, the major asymmetric arginine methyltransferase, 
        is a positive regulator of longevity in C. elegans
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21531333
  review:
    summary: 'Nuclear localization demonstrated with PRMT-1 regulation.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: PRMT-1 methylates DAF-16, thereby blocking its 
        phosphorylation by AKT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21531333
  review:
    summary: 'Cytoplasmic localization under normal conditions.

      '
    action: ACCEPT
    reason: 'Direct evidence of cytoplasmic localization.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1, the major asymmetric arginine methyltransferase, 
        is a positive regulator of longevity in C. elegans
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: 'DAF-16 mediates oxidative stress responses through PRMT-1.

      '
    action: ACCEPT
    reason: 'Oxidative stress response is core DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1 is also required for stress tolerance
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: 'DAF-16 contributes to UV stress response.

      '
    action: ACCEPT
    reason: 'UV response is part of DAF-16 stress response functions.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1 is also required for stress tolerance
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:21531333
  review:
    summary: 'DAF-16 activates longevity-related gene expression.

      '
    action: ACCEPT
    reason: 'Consistent with transcriptional activator function.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: Disruption of PRMT-1 induces phosphorylation of DAF-16 
        with a concomitant reduction in the expression of longevity-related 
        genes
- term:
    id: GO:0010883
    label: regulation of lipid storage
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: 'DAF-16 regulates fat storage through PRMT-1 pathway.

      '
    action: ACCEPT
    reason: 'Lipid metabolism is a documented DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1 is also required for stress tolerance and fat 
        storage
- term:
    id: GO:1905909
    label: regulation of dauer entry
  evidence_type: IGI
  original_reference_id: PMID:21531333
  review:
    summary: 'DAF-16 regulates dauer formation.

      '
    action: ACCEPT
    reason: 'Dauer regulation is core DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:21531333
      supporting_text: prmt-1 is also required for stress tolerance and fat 
        storage but not dauer formation
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:17277769
  review:
    summary: 'DAF-16 is required for lifespan extension by eIF4E reduction.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:17277769
    supported_by:
    - reference_id: PMID:17277769
      supporting_text: eIF4E function in somatic cells modulates ageing in 
        Caenorhabditis elegans.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:17277769
  review:
    summary: 'Genetic interaction with eIF4E for lifespan.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:17277769
    supported_by:
    - reference_id: PMID:17277769
      supporting_text: eIF4E function in somatic cells modulates ageing in 
        Caenorhabditis elegans.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:27001890
  review:
    summary: 'DAF-16 contributes to longevity in response to gonadal signals.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:27001890
    supported_by:
    - reference_id: PMID:27001890
      supporting_text: Mondo complexes regulate TFEB via TOR inhibition to 
        promote longevity in response to gonadal signals.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:24957743
  review:
    summary: 'Nuclear localization in ZMP-2 study.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    additional_reference_ids:
    - PMID:24957743
    supported_by:
    - reference_id: PMID:24957743
      supporting_text: The zinc matrix metalloproteinase ZMP-2 increases 
        survival of Caenorhabditis elegans through interference with lipoprotein
        absorption.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24957743
  review:
    summary: 'Cytoplasmic localization in ZMP-2 study.

      '
    action: ACCEPT
    reason: 'Direct evidence of cytoplasmic localization.

      '
    additional_reference_ids:
    - PMID:24957743
    supported_by:
    - reference_id: PMID:24957743
      supporting_text: The zinc matrix metalloproteinase ZMP-2 increases 
        survival of Caenorhabditis elegans through interference with lipoprotein
        absorption.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:27564576
  review:
    summary: 'DAF-16 affects lifespan in CNNM pathway study.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:27564576
    supported_by:
    - reference_id: PMID:27564576
      supporting_text: eCollection 2016 Aug.
- term:
    id: GO:0017151
    label: DEAD/H-box RNA helicase binding
  evidence_type: IPI
  original_reference_id: PMID:26195740
  review:
    summary: 'DAF-16 interacts with RNA helicase HEL-1, which promotes its activity.

      '
    action: ACCEPT
    reason: 'Specific protein binding interaction documented by co-IP.

      '
    additional_reference_ids:
    - PMID:26195740
    supported_by:
    - reference_id: PMID:26195740
      supporting_text: RNA helicase HEL-1 promotes longevity by specifically 
        activating DAF-16/FOXO transcription factor signaling in Caenorhabditis 
        elegans.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:23028355
  review:
    summary: 'DAF-16 interacts with SIR-2.4 sirtuin enzyme.

      '
    action: ACCEPT
    reason: 'Documented protein interaction with enzymatic regulator.

      '
    additional_reference_ids:
    - PMID:23028355
    supported_by:
    - reference_id: PMID:23028355
      supporting_text: 2012 Sep 13. C. elegans SIRT6/7 homolog SIR-2.4 promotes 
        DAF-16 relocalization and function during stress.
- term:
    id: GO:0061065
    label: regulation of dauer larval development
  evidence_type: IGI
  original_reference_id: PMID:21124868
  review:
    summary: 'DAF-16 regulates dauer development in context of DAF-25.

      '
    action: ACCEPT
    reason: 'Dauer regulation is core DAF-16 function.

      '
    additional_reference_ids:
    - PMID:21124868
    supported_by:
    - reference_id: PMID:21124868
      supporting_text: Localization of a guanylyl cyclase to chemosensory cilia 
        requires the novel ciliary MYND domain protein DAF-25.
- term:
    id: GO:0061065
    label: regulation of dauer larval development
  evidence_type: IGI
  original_reference_id: PMID:1732156
  review:
    summary: 'Original genetic evidence placing daf-16 in dauer pathway.

      '
    action: ACCEPT
    reason: 'Foundational evidence for dauer regulation function.

      '
    supported_by:
    - reference_id: PMID:1732156
      supporting_text: Three genes, daf-16, daf-18 and daf-20, may affect 
        downstream steps in a branched part of the pathway
- term:
    id: GO:0007614
    label: short-term memory
  evidence_type: IGI
  original_reference_id: PMID:26675724
  review:
    summary: 'DAF-16 contributes to associative memory in neurons.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Memory function is a secondary/pleiotropic effect. Not a core function
      but documented.

      '
    additional_reference_ids:
    - PMID:26675724
    supported_by:
    - reference_id: PMID:26675724
      supporting_text: The C. elegans adult neuronal IIS/FOXO transcriptome 
        reveals adult phenotype regulators.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:23352664
  review:
    summary: 'DAF-16 mediates lifespan extension by fasting signaling.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:23352664
    supported_by:
    - reference_id: PMID:23352664
      supporting_text: Jan 24. A fasting-responsive signaling pathway that 
        extends life span in C.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:23352664
  review:
    summary: 'Genetic interaction for lifespan with fasting pathway.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:23352664
    supported_by:
    - reference_id: PMID:23352664
      supporting_text: Jan 24. A fasting-responsive signaling pathway that 
        extends life span in C.
- term:
    id: GO:0042594
    label: response to starvation
  evidence_type: IMP
  original_reference_id: PMID:23352664
  review:
    summary: 'DAF-16 mediates fasting/starvation responses.

      '
    action: ACCEPT
    reason: 'Starvation response is core DAF-16 function.

      '
    additional_reference_ids:
    - PMID:23352664
    supported_by:
    - reference_id: PMID:23352664
      supporting_text: Jan 24. A fasting-responsive signaling pathway that 
        extends life span in C.
- term:
    id: GO:1900426
    label: positive regulation of defense response to bacterium
  evidence_type: IMP
  original_reference_id: PMID:22554143
  review:
    summary: 'DAF-16 promotes antibacterial defense with JNK signaling.

      '
    action: ACCEPT
    reason: 'Innate immunity is core DAF-16 function.

      '
    additional_reference_ids:
    - PMID:22554143
    supported_by:
    - reference_id: PMID:22554143
      supporting_text: 2012 May 30. An age-dependent reversal in the protective 
        capacities of JNK signaling shortens Caenorhabditis elegans lifespan.
- term:
    id: GO:0008013
    label: beta-catenin binding
  evidence_type: IPI
  original_reference_id: PMID:15905404
  review:
    summary: 'DAF-16 binds to beta-catenin BAR-1, which enhances its transcriptional
      activity during oxidative stress.

      '
    action: ACCEPT
    reason: 'Specific protein binding documented that is functionally important for
      oxidative stress response.

      '
    supported_by:
    - reference_id: PMID:15905404
      supporting_text: beta-Catenin binds directly to FOXO and enhances FOXO 
        transcriptional activity
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:15905404
  review:
    summary: 'BAR-1/beta-catenin affects DAF-16-dependent lifespan.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    supported_by:
    - reference_id: PMID:15905404
      supporting_text: loss of the beta-catenin BAR-1 reduces the activity of 
        the FOXO ortholog DAF-16 in dauer formation and life span
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IGI
  original_reference_id: PMID:15905404
  review:
    summary: 'DAF-16 with BAR-1 mediates oxidative stress response.

      '
    action: ACCEPT
    reason: 'Oxidative stress response is core DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:15905404
      supporting_text: BAR-1 was required for the oxidative stress-induced 
        expression of the DAF-16 target gene sod-3
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IGI
  original_reference_id: PMID:15905404
  review:
    summary: 'DAF-16 with BAR-1 regulates dauer development.

      '
    action: ACCEPT
    reason: 'Dauer regulation is core DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:15905404
      supporting_text: loss of the beta-catenin BAR-1 reduces the activity of 
        the FOXO ortholog DAF-16 in dauer formation
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:15905404
  review:
    summary: 'DAF-16 activates transcription with BAR-1 enhancement.

      '
    action: ACCEPT
    reason: 'Core transcriptional activator function.

      '
    supported_by:
    - reference_id: PMID:15905404
      supporting_text: beta-Catenin binds directly to FOXO and enhances FOXO 
        transcriptional activity
- term:
    id: GO:1990381
    label: ubiquitin-specific protease binding
  evidence_type: IPI
  original_reference_id: PMID:26154057
  review:
    summary: 'DAF-16 binds to MATH-33 deubiquitinase, which stabilizes it.

      '
    action: ACCEPT
    reason: 'Specific protein binding with regulatory importance.

      '
    additional_reference_ids:
    - PMID:26154057
    supported_by:
    - reference_id: PMID:26154057
      supporting_text: The Deubiquitylase MATH-33 Controls DAF-16 Stability and 
        Function in Metabolism and Longevity.
- term:
    id: GO:0061066
    label: positive regulation of dauer larval development
  evidence_type: IMP
  original_reference_id: PMID:6583682
  review:
    summary: 'DAF-16 promotes dauer formation; daf-16 mutants are dauer-defective.

      '
    action: ACCEPT
    reason: 'Core function in dauer development pathway.

      '
    additional_reference_ids:
    - PMID:6583682
    supported_by:
    - reference_id: PMID:6583682
      supporting_text: 'A pheromone-induced developmental switch in Caenorhabditis
        elegans: Temperature-sensitive mutants reveal a wild-type temperature-dependent
        process.'
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IDA
  original_reference_id: PMID:22922647
  review:
    summary: 'DAF-16 acts as transcription factor to activate rpn-6.1 expression.

      '
    action: ACCEPT
    reason: 'Core molecular function.

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: increased expression of rpn-6, a subunit of the 19S 
        proteasome, by the FOXO transcription factor DAF-16
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IDA
  original_reference_id: PMID:22922647
  review:
    summary: 'DAF-16 contributes to proteotoxic stress response including DNA damage.

      '
    action: KEEP_AS_NON_CORE
    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.

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: RPN-6 determines C. elegans longevity under proteotoxic 
        stress conditions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23255046
  review:
    summary: 'DAF-16 interacts with NSBP-1 (nucleosome binding protein).

      '
    action: MODIFY
    reason: '"Protein binding" is too generic. Should be more specific if possible.

      '
    proposed_replacement_terms:
    - id: GO:0044877
      label: protein-containing complex binding
    additional_reference_ids:
    - PMID:23255046
    supported_by:
    - reference_id: PMID:23255046
      supporting_text: Epub 2012 Dec 20. NSBP-1 mediates the effects of 
        cholesterol on insulin/IGF-1 signaling in Caenorhabditis elegans.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22922647
  review:
    summary: 'Nuclear localization in proteotoxic stress study.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: RPN-6 determines C. elegans longevity under proteotoxic 
        stress conditions
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:22922647
  review:
    summary: 'Cytosolic localization (more specific than cytoplasm).

      '
    action: ACCEPT
    reason: 'Direct evidence of cytosolic localization.

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: RPN-6 determines C. elegans longevity under proteotoxic 
        stress conditions
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IDA
  original_reference_id: PMID:22922647
  review:
    summary: 'DAF-16 directly regulates longevity genes including rpn-6.1.

      '
    action: ACCEPT
    reason: 'Core longevity function demonstrated by direct assay.

      '
    supported_by:
    - reference_id: PMID:22922647
      supporting_text: increased expression of rpn-6, a subunit of the 19S 
        proteasome, by the FOXO transcription factor DAF-16
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:22560223
  review:
    summary: 'DAF-16 required for lifespan effects of TOR signaling.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:22560223
    supported_by:
    - reference_id: PMID:22560223
      supporting_text: TOR signaling and rapamycin influence longevity by 
        regulating SKN-1/Nrf and DAF-16/FoxO.
- term:
    id: GO:0040015
    label: negative regulation of multicellular organism growth
  evidence_type: IMP
  original_reference_id: PMID:12571101
  review:
    summary: 'DAF-16 contributes to growth regulation with EGL-4/cGMP-dependent kinase.

      '
    action: ACCEPT
    reason: 'Growth regulation is documented DAF-16 function.

      '
    additional_reference_ids:
    - PMID:12571101
    supported_by:
    - reference_id: PMID:12571101
      supporting_text: Cyclic GMP-dependent protein kinase EGL-4 controls body 
        size and lifespan in C elegans.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:20523893
  review:
    summary: 'DAF-16 genetic interaction with RAGA-1 for lifespan.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    additional_reference_ids:
    - PMID:20523893
    supported_by:
    - reference_id: PMID:20523893
      supporting_text: Manipulation of behavioral decline in Caenorhabditis 
        elegans with the Rag GTPase raga-1.
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IMP
  original_reference_id: PMID:19454349
  review:
    summary: 'DAF-16 required for innate immunity during EPEC conditioning.

      '
    action: ACCEPT
    reason: 'Core innate immunity function demonstrated with mutant phenotype.

      '
    supported_by:
    - reference_id: PMID:19454349
      supporting_text: Conditioning requires... the insulin/IGFR pathway, which 
        regulates lifespan
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:19454349
  review:
    summary: 'DAF-16 activates transcription of immune genes during conditioning.

      '
    action: ACCEPT
    reason: 'Core transcriptional activator function.

      '
    supported_by:
    - reference_id: PMID:19454349
      supporting_text: Conditioning protects C. elegans from lethal effects of 
        enteropathogenic E. coli by activating genes
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:19103192
  review:
    summary: 'DAF-16 interacts with HLH-13 transcription factor.

      '
    action: ACCEPT
    reason: 'Documented interaction between transcription factors.

      '
    additional_reference_ids:
    - PMID:19103192
    supported_by:
    - reference_id: PMID:19103192
      supporting_text: 2008 Dec 7. Combined informatic and expression screen 
        identifies the novel DAF-16 target HLH-13.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:19252938
  review:
    summary: 'Nuclear localization demonstrated with ROS-generator treatment.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    additional_reference_ids:
    - PMID:19252938
    supported_by:
    - reference_id: PMID:19252938
      supporting_text: Feeding a ROS-generator to Caenorhabditis elegans leads 
        to increased expression of small heat shock protein HSP-16.2 and 
        hormesis.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:17894411
  review:
    summary: 'DAF-16 regulates transcription with JNK-1 input.

      '
    action: ACCEPT
    reason: 'Core transcription regulation function.

      '
    additional_reference_ids:
    - PMID:17894411
    supported_by:
    - reference_id: PMID:17894411
      supporting_text: 'The MAP kinase JNK-1 of Caenorhabditis elegans: location,
        activation, and influences over temperature-dependent insulin-like signaling,
        stress responses, and fitness.'
- term:
    id: GO:0002821
    label: positive regulation of adaptive immune response
  evidence_type: IMP
  original_reference_id: PMID:18245330
  review:
    summary: 'DAF-16 suppresses immunity during reproduction.

      '
    action: MODIFY
    reason: 'C. elegans does not have adaptive immunity. This term is inappropriate
      for a nematode. Should use innate immunity term.

      '
    proposed_replacement_terms:
    - id: GO:0045087
      label: innate immune response
    additional_reference_ids:
    - PMID:18245330
    supported_by:
    - reference_id: PMID:18245330
      supporting_text: Feb 1. DAF-16-dependent suppression of immunity during 
        reproduction in Caenorhabditis elegans.
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:17934462
  review:
    summary: 'DAF-16 promotes apoptosis in germline tumor model.

      '
    action: ACCEPT
    reason: 'Documented effect on apoptosis in tumor context.

      '
    supported_by:
    - reference_id: PMID:17934462
      supporting_text: DAF-16/FOXO targets genes that regulate tumor growth in 
        Caenorhabditis elegans
- term:
    id: GO:0046890
    label: regulation of lipid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:18762027
  review:
    summary: 'DAF-16 regulates lipogenesis downstream of IIS.

      '
    action: ACCEPT
    reason: 'Lipid metabolism is documented DAF-16 function.

      '
    additional_reference_ids:
    - PMID:18762027
    supported_by:
    - reference_id: PMID:18762027
      supporting_text: A 13C isotope labeling strategy reveals the influence of 
        insulin signaling on lipogenesis in C.
- term:
    id: GO:0060537
    label: muscle tissue development
  evidence_type: IMP
  original_reference_id: PMID:18397876
  review:
    summary: 'DAF-16 affects muscle in polyalanine muscular dystrophy model.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Muscle function is secondary/pleiotropic. DAF-16 is not a muscle-specific
      regulator.

      '
    additional_reference_ids:
    - PMID:18397876
    supported_by:
    - reference_id: PMID:18397876
      supporting_text: Apr 7. Sirtuin inhibition protects from the polyalanine 
        muscular dystrophy protein PABPN1.
- term:
    id: GO:0002119
    label: nematode larval development
  evidence_type: IMP
  original_reference_id: PMID:11747821
  review:
    summary: 'DAF-16 affects larval development and dauer decision.

      '
    action: ACCEPT
    reason: 'Developmental regulation is core DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:11747821
      supporting_text: C. elegans insulin-like signaling regulates metabolism, 
        development, and life span
- term:
    id: GO:0002821
    label: positive regulation of adaptive immune response
  evidence_type: IMP
  original_reference_id: PMID:17096597
  review:
    summary: 'DAF-16 contributes to immune response.

      '
    action: MODIFY
    reason: 'C. elegans does not have adaptive immunity. Should use innate immunity.

      '
    proposed_replacement_terms:
    - id: GO:0045087
      label: innate immune response
    supported_by:
    - reference_id: PMID:17096597
      supporting_text: p38 MAPK regulates expression of immune response genes 
        and contributes to longevity in C. elegans
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:11747821
  review:
    summary: 'Nuclear localization demonstrated with GFP fusion.

      '
    action: ACCEPT
    reason: 'Direct evidence of nuclear localization.

      '
    supported_by:
    - reference_id: PMID:11747821
      supporting_text: daf-2 insulin signaling, via AKT kinases, negatively 
        regulates DAF-16 by controlling its nuclear localization
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11381260
  review:
    summary: 'Cytoplasmic localization under fed conditions.

      '
    action: ACCEPT
    reason: 'Direct evidence of cytoplasmic localization.

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: Here, we show that the DAF-2 pathway prevents DAF-16 
        accumulation in nuclei
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11747821
  review:
    summary: 'Cytoplasmic localization with DAF-2 signaling.

      '
    action: ACCEPT
    reason: 'Direct evidence of cytoplasmic localization.

      '
    supported_by:
    - reference_id: PMID:11747821
      supporting_text: daf-2 insulin signaling, via AKT kinases, negatively 
        regulates DAF-16 by controlling its nuclear localization
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:17096597
  review:
    summary: 'DAF-16 regulates transcription of immune genes.

      '
    action: ACCEPT
    reason: 'Core transcription regulation function.

      '
    supported_by:
    - reference_id: PMID:17096597
      supporting_text: p38 MAPK regulates expression of immune response genes
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:11747821
  review:
    summary: 'DAF-16 is major output of insulin receptor signaling in C. elegans.

      '
    action: ACCEPT
    reason: 'Core pathway annotation well-supported by literature.

      '
    supported_by:
    - reference_id: PMID:11747821
      supporting_text: C. elegans insulin-like signaling regulates metabolism, 
        development, and life span
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:11381260
  review:
    summary: 'daf-16 mutants suppress lifespan extension of daf-2 mutants.

      '
    action: ACCEPT
    reason: 'Foundational evidence for DAF-16 longevity function.

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: This lifespan extension requires DAF-16
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:11747821
  review:
    summary: 'DAF-16 required for lifespan extension.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    supported_by:
    - reference_id: PMID:11747821
      supporting_text: C. elegans insulin-like signaling regulates metabolism, 
        development, and life span
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IDA
  original_reference_id: PMID:11747825
  review:
    summary: 'DAF-16 responds to UV stress.

      '
    action: ACCEPT
    reason: 'UV stress response is part of general stress response function.

      '
    supported_by:
    - reference_id: PMID:11747825
      supporting_text: Environmental stresses, such as starvation, heat, and 
        oxidative stress, cause rapid nuclear localization of DAF-16
- term:
    id: GO:0010564
    label: regulation of cell cycle process
  evidence_type: IEP
  original_reference_id: PMID:17934462
  review:
    summary: 'DAF-16 affects cell cycle in germline tumor model.

      '
    action: KEEP_AS_NON_CORE
    reason: 'Cell cycle regulation is secondary to tumor suppressor function. IEP
      evidence is weaker.

      '
    supported_by:
    - reference_id: PMID:17934462
      supporting_text: DAF-16/FOXO targets genes that regulate tumor growth
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:17276341
  review:
    summary: 'DAF-16 interacts with RLE-1 E3 ubiquitin ligase that ubiquitinates it.

      '
    action: ACCEPT
    reason: 'Specific protein binding with regulatory importance for DAF-16 turnover.

      '
    additional_reference_ids:
    - PMID:17276341
    supported_by:
    - reference_id: PMID:17276341
      supporting_text: RLE-1, an E3 ubiquitin ligase, regulates C.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:11381260
  review:
    summary: 'Heat stress causes DAF-16 nuclear accumulation.

      '
    action: ACCEPT
    reason: 'Heat stress response is core DAF-16 function.

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: We find that both sensory neurons and germline activity 
        regulate DAF-16 accumulation in nuclei
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:11747825
  review:
    summary: 'Heat stress induces DAF-16 nuclear translocation.

      '
    action: ACCEPT
    reason: 'Core stress response function.

      '
    supported_by:
    - reference_id: PMID:11747825
      supporting_text: Environmental stresses, such as starvation, heat, and 
        oxidative stress, cause rapid nuclear localization of DAF-16
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11124266
  review:
    summary: 'DAF-16 interacts with 14-3-3 proteins.

      '
    action: MODIFY
    reason: '"Protein binding" is too generic. This is 14-3-3 binding specifically.

      '
    proposed_replacement_terms:
    - id: GO:0071889
      label: 14-3-3 protein binding
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: AKT phosphorylation generates 14-3-3 binding sites and 
        regulates the nuclear/cytoplasmic distribution of DAF-16
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:11124266
  review:
    summary: 'DAF-16 is directly phosphorylated by AKT downstream of insulin signaling.

      '
    action: ACCEPT
    reason: 'Core pathway annotation. Direct biochemical evidence.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: C. elegans DAF-16 is a direct target of AKT
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:11381260
  review:
    summary: 'Genetic interaction with daf-2 for lifespan.

      '
    action: ACCEPT
    reason: 'Core longevity function.

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: This lifespan extension requires DAF-16
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:11124266
  review:
    summary: 'DAF-16 activates transcription through DNA binding.

      '
    action: ACCEPT
    reason: 'Core transcriptional activator function demonstrated directly.

      '
    supported_by:
    - reference_id: PMID:11124266
      supporting_text: a GAL4 DNA binding domain/DAF-16 fusion protein to 
        activate transcription
- term:
    id: GO:0040024
    label: dauer larval development
  evidence_type: IGI
  original_reference_id: PMID:11381260
  review:
    summary: 'DAF-16 regulates dauer formation.

      '
    action: ACCEPT
    reason: 'Core developmental function.

      '
    supported_by:
    - reference_id: PMID:11381260
      supporting_text: Together these findings reveal unexpected complexity in 
        the DAF-16-dependent pathways that regulate aging
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: PMID:11124266
  title: Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and
    function via 14-3-3-dependent and 14-3-3-independent pathways.
  findings:
  - statement: DAF-16 is a direct target of AKT phosphorylation
    supporting_text: Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA
      binding and function via 14-3-3-dependent and 14-3-3-independent pathways.
  - statement: AKT phosphorylation generates 14-3-3 binding sites
    supporting_text: Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA
      binding and function via 14-3-3-dependent and 14-3-3-independent pathways.
  - statement: 14-3-3 binding regulates nuclear/cytoplasmic distribution
    supporting_text: Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA
      binding and function via 14-3-3-dependent and 14-3-3-independent pathways.
  - statement: 14-3-3 binding inhibits DAF-16 DNA binding
    supporting_text: Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA
      binding and function via 14-3-3-dependent and 14-3-3-independent pathways.
  - statement: PI 3-kinase/AKT signaling inhibits DAF-16 transcription activity
    supporting_text: Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA
      binding and function via 14-3-3-dependent and 14-3-3-independent pathways.
- id: PMID:11381260
  title: Regulation of the Caenorhabditis elegans longevity protein DAF-16 by 
    insulin/IGF-1 and germline signaling.
  findings:
  - statement: DAF-2 pathway prevents DAF-16 nuclear accumulation
    supporting_text: Regulation of the Caenorhabditis elegans longevity protein 
      DAF-16 by insulin/IGF-1 and germline signaling.
  - statement: Disrupting AKT phosphorylation sites causes nuclear accumulation
    supporting_text: Regulation of the Caenorhabditis elegans longevity protein 
      DAF-16 by insulin/IGF-1 and germline signaling.
  - statement: Both sensory neurons and germline regulate DAF-16 localization
    supporting_text: Regulation of the Caenorhabditis elegans longevity protein 
      DAF-16 by insulin/IGF-1 and germline signaling.
  - statement: DAF-16 required for lifespan extension in daf-2 mutants
    supporting_text: Regulation of the Caenorhabditis elegans longevity protein 
      DAF-16 by insulin/IGF-1 and germline signaling.
- id: PMID:11747821
  title: Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the 
    daf-2 insulin-like signaling pathway.
  findings:
  - statement: Human FKHRL1 can partially replace DAF-16
    supporting_text: Regulation of C. elegans DAF-16 and its human ortholog 
      FKHRL1 by the daf-2 insulin-like signaling pathway.
  - statement: DAF-16 is major output of insulin signaling
    supporting_text: Regulation of C. elegans DAF-16 and its human ortholog 
      FKHRL1 by the daf-2 insulin-like signaling pathway.
  - statement: daf-2 insulin signaling via AKT controls DAF-16 nuclear 
      localization
    supporting_text: Regulation of C. elegans DAF-16 and its human ortholog 
      FKHRL1 by the daf-2 insulin-like signaling pathway.
  - statement: daf-7 TGF-beta signaling also regulates DAF-16 localization
    supporting_text: Regulation of C. elegans DAF-16 and its human ortholog 
      FKHRL1 by the daf-2 insulin-like signaling pathway.
- id: PMID:11747825
  title: daf-16 integrates developmental and environmental inputs to mediate 
    aging in the nematode Caenorhabditis elegans.
  findings:
  - statement: DAF-16::GFP worms grow slower but live longer
    supporting_text: daf-16 integrates developmental and environmental inputs to
      mediate aging in the nematode Caenorhabditis elegans.
  - statement: Starvation, heat, and oxidative stress cause DAF-16 nuclear 
      localization
    supporting_text: daf-16 integrates developmental and environmental inputs to
      mediate aging in the nematode Caenorhabditis elegans.
  - statement: DAF-16 is inhibited from nuclear entry by daf-2 and akt-1/akt-2
    supporting_text: daf-16 integrates developmental and environmental inputs to
      mediate aging in the nematode Caenorhabditis elegans.
- id: PMID:15068796
  title: C. elegans SGK-1 is the critical component in the Akt/PKB kinase 
    complex to control stress response and life span.
  findings:
  - statement: SGK-1 forms complex with AKT kinases
    supporting_text: C. elegans SGK-1 is the critical component in the Akt/PKB 
      kinase complex to control stress response and life span.
  - statement: All three kinases phosphorylate DAF-16
    supporting_text: C. elegans SGK-1 is the critical component in the Akt/PKB 
      kinase complex to control stress response and life span.
  - statement: SGK-1 is crucial for control of stress response and longevity
    supporting_text: C. elegans SGK-1 is the critical component in the Akt/PKB 
      kinase complex to control stress response and life span.
- id: PMID:15905404
  title: Functional interaction between beta-catenin and FOXO in oxidative 
    stress signaling.
  findings:
  - statement: Beta-catenin binds directly to FOXO
    supporting_text: Functional interaction between beta-catenin and FOXO in 
      oxidative stress signaling.
  - statement: BAR-1 enhances DAF-16 transcriptional activity
    supporting_text: Functional interaction between beta-catenin and FOXO in 
      oxidative stress signaling.
  - statement: BAR-1 required for oxidative stress-induced sod-3 expression
    supporting_text: Functional interaction between beta-catenin and FOXO in 
      oxidative stress signaling.
  - statement: Loss of BAR-1 reduces DAF-16 activity in dauer formation and 
      lifespan
    supporting_text: Functional interaction between beta-catenin and FOXO in 
      oxidative stress signaling.
- id: PMID:16777605
  title: C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 
    and extend life span.
  findings:
  - statement: Two 14-3-3 proteins are SIR-2.1 binding partners
    supporting_text: C. elegans SIR-2.1 interacts with 14-3-3 proteins to 
      activate DAF-16 and extend life span.
  - statement: 14-3-3 required for sir-2.1-induced life-span extension
    supporting_text: C. elegans SIR-2.1 interacts with 14-3-3 proteins to 
      activate DAF-16 and extend life span.
  - statement: SIR-2.1 can bind DAF-16 in 14-3-3-dependent manner after heat 
      stress
    supporting_text: C. elegans SIR-2.1 interacts with 14-3-3 proteins to 
      activate DAF-16 and extend life span.
- id: PMID:17098225
  title: The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis elegans.
  findings:
  - statement: FTT-2 knockdown causes DAF-16 nuclear accumulation
    supporting_text: The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis
      elegans.
  - statement: FTT-2 forms complex with DAF-16
    supporting_text: The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis
      elegans.
  - statement: FTT-2 regulates DAF-16 by cytoplasmic sequestration
    supporting_text: The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis
      elegans.
- id: PMID:17934462
  title: DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis 
    elegans.
  findings:
  - statement: DAF-16 targets genes that regulate tumor growth
    supporting_text: DAF-16/FOXO targets genes that regulate tumor growth in 
      Caenorhabditis elegans.
  - statement: Many genes also affect normal aging
    supporting_text: DAF-16/FOXO targets genes that regulate tumor growth in 
      Caenorhabditis elegans.
  - statement: DAF-16 regulates p53-dependent apoptosis
    supporting_text: DAF-16/FOXO targets genes that regulate tumor growth in 
      Caenorhabditis elegans.
- id: PMID:18358814
  title: Direct inhibition of the longevity-promoting factor SKN-1 by 
    insulin-like signaling in C. elegans.
  findings:
  - statement: IIS kinases AKT-1, -2, and SGK-1 phosphorylate both DAF-16 and 
      SKN-1
    supporting_text: Direct inhibition of the longevity-promoting factor SKN-1 
      by insulin-like signaling in C. elegans.
  - statement: Reduced IIS leads to DAF-16 nuclear accumulation
    supporting_text: Direct inhibition of the longevity-promoting factor SKN-1 
      by insulin-like signaling in C. elegans.
- id: PMID:19454349
  title: Conditioning protects C. elegans from lethal effects of 
    enteropathogenic E. coli by activating genes that regulate lifespan and 
    innate immunity.
  findings:
  - statement: Conditioning requires the insulin/IGFR pathway
    supporting_text: Conditioning protects C. elegans from lethal effects of 
      enteropathogenic E. coli by activating genes that regulate lifespan and 
      innate immunity.
  - statement: DAF-16 contributes to pathogen resistance
    supporting_text: Conditioning protects C. elegans from lethal effects of 
      enteropathogenic E. coli by activating genes that regulate lifespan and 
      innate immunity.
- id: PMID:21531333
  title: Asymmetric arginine dimethylation determines life span in C. elegans by
    regulating forkhead transcription factor DAF-16.
  findings:
  - statement: PRMT-1 methylates DAF-16, blocking phosphorylation by AKT
    supporting_text: Asymmetric arginine dimethylation determines life span in 
      C. elegans by regulating forkhead transcription factor DAF-16.
  - statement: Methylation promotes DAF-16 nuclear translocation
    supporting_text: Asymmetric arginine dimethylation determines life span in 
      C. elegans by regulating forkhead transcription factor DAF-16.
  - statement: prmt-1 required for stress tolerance and fat storage
    supporting_text: Asymmetric arginine dimethylation determines life span in 
      C. elegans by regulating forkhead transcription factor DAF-16.
  - statement: FTT-2 sequesters DAF-16 in cytoplasm
    supporting_text: Asymmetric arginine dimethylation determines life span in 
      C. elegans by regulating forkhead transcription factor DAF-16.
- id: PMID:22922647
  title: RPN-6 determines C. elegans longevity under proteotoxic stress 
    conditions.
  findings:
  - statement: DAF-16 activates rpn-6 expression
    supporting_text: RPN-6 determines C. elegans longevity under proteotoxic 
      stress conditions.
  - statement: rpn-6 is sufficient for proteotoxic stress resistance
    supporting_text: RPN-6 determines C. elegans longevity under proteotoxic 
      stress conditions.
  - statement: DAF-16 enhances 26S proteasome assembly
    supporting_text: RPN-6 determines C. elegans longevity under proteotoxic 
      stress conditions.
- id: PMID:1732156
  title: Genetic analysis of chemosensory control of dauer formation in 
    Caenorhabditis elegans.
  findings:
  - statement: daf-16 affects downstream steps in dauer pathway
    supporting_text: Genetic analysis of chemosensory control of dauer formation
      in Caenorhabditis elegans.
  - statement: Epistasis analysis places daf-16 in linear pathway
    supporting_text: Genetic analysis of chemosensory control of dauer formation
      in Caenorhabditis elegans.
- id: PMID:16860373
  title: C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1
    and DAF-16/FOXO.
  findings:
  - statement: 14-3-3 proteins regulate DAF-16/FOXO and SIR-2.1
    supporting_text: C. elegans 14-3-3 proteins regulate life span and interact 
      with SIR-2.1 and DAF-16/FOXO.
- id: PMID:19506556
  title: A soma-to-germline transformation in long-lived Caenorhabditis elegans 
    mutants.
  findings:
  - statement: DAF-16 ChIP analysis in germline-less mutants
    supporting_text: A soma-to-germline transformation in long-lived 
      Caenorhabditis elegans mutants.
  - statement: Germline removal causes soma-to-germline transformation
    supporting_text: A soma-to-germline transformation in long-lived 
      Caenorhabditis elegans mutants.
- id: PMID:23911329
  title: PQM-1 complements DAF-16 as a key transcriptional regulator of 
    DAF-2-mediated development and longevity.
  findings:
  - statement: PQM-1 and DAF-16 regulate non-overlapping gene sets
    supporting_text: PQM-1 complements DAF-16 as a key transcriptional regulator
      of DAF-2-mediated development and longevity.
  - statement: Nuclear localization of DAF-16 and PQM-1 are mutually exclusive
    supporting_text: PQM-1 complements DAF-16 as a key transcriptional regulator
      of DAF-2-mediated development and longevity.
- id: PMID:26154057
  title: The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in 
    Metabolism and Longevity.
  findings:
  - statement: MATH-33 deubiquitinase binds and stabilizes DAF-16
    supporting_text: The Deubiquitylase MATH-33 Controls DAF-16 Stability and 
      Function in Metabolism and Longevity.
  - statement: DAF-16 nuclear localization is affected by MATH-33
    supporting_text: The Deubiquitylase MATH-33 Controls DAF-16 Stability and 
      Function in Metabolism and Longevity.
- id: PMID:12750521
  title: Regulation of aging and age-related disease by DAF-16 and heat-shock 
    factor.
  findings:
  - statement: DAF-16 and HSF-1 work together for longevity
    supporting_text: Regulation of aging and age-related disease by DAF-16 and 
      heat-shock factor.
  - statement: Both transcription factors regulate stress responses
    supporting_text: Regulation of aging and age-related disease by DAF-16 and 
      heat-shock factor.
- id: PMID:26963674
  title: "A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. elegans
    vit-2 vitellogenin gene is directly regulated by ELT-2, MAB-3, FKH-9 and DAF-16
    and indirectly regulated by the germline, by daf-2/insulin signaling and by the
    TGF-β/Sma/Mab pathway."
  findings:
  - statement: DAF-16 represses vit-2 expression in intestine
    supporting_text: A 44 bp intestine-specific hermaphrodite-specific enhancer 
      from the C. elegans vit-2 vitellogenin gene is directly regulated by 
      ELT-2, MAB-3, FKH-9 and DAF-16 and indirectly regulated by the germline, 
      by daf-2/insulin signaling and by the TGF-β/Sma/Mab pathway.
  - statement: DAF-16 has post-developmental functions
    supporting_text: A 44 bp intestine-specific hermaphrodite-specific enhancer 
      from the C. elegans vit-2 vitellogenin gene is directly regulated by 
      ELT-2, MAB-3, FKH-9 and DAF-16 and indirectly regulated by the germline, 
      by daf-2/insulin signaling and by the TGF-β/Sma/Mab pathway.
- id: PMID:16916933
  title: Heat-shock transcription factor (HSF)-1 pathway required for 
    Caenorhabditis elegans immunity.
  findings:
  - statement: DAF-16 and HSF-1 act synergistically for innate immunity
    supporting_text: Heat-shock transcription factor (HSF)-1 pathway required 
      for Caenorhabditis elegans immunity.
  - statement: Defense response to Gram-negative bacteria requires both factors
    supporting_text: Heat-shock transcription factor (HSF)-1 pathway required 
      for Caenorhabditis elegans immunity.
- id: PMID:32963007
  title: Intergenerational pathogen-induced diapause in Caenorhabditis elegans 
    is modulated by mir-243.
  findings:
  - statement: DAF-16 regulates gene expression in intergenerational responses
    supporting_text: Intergenerational Pathogen-Induced Diapause in 
      Caenorhabditis elegans Is Modulated by mir-243.
- id: PMID:29523076
  title: Normal sleep bouts are not essential for C. elegans survival and FoxO 
    is important for compensatory changes in sleep.
  findings:
  - statement: DAF-16 contributes to sleep regulation in C. elegans
    supporting_text: Normal sleep bouts are not essential for C. elegans 
      survival and FoxO is important for compensatory changes in sleep.
- id: PMID:25330323
  title: The DAF-16 FOXO transcription factor regulates natc-1 to modulate 
    stress resistance in Caenorhabditis elegans, linking insulin/IGF-1 signaling
    to protein N-terminal acetylation.
  findings:
  - statement: DAF-16 represses natc-1 expression
    supporting_text: The DAF-16 FOXO transcription factor regulates natc-1 to 
      modulate stress resistance in Caenorhabditis elegans, linking 
      insulin/IGF-1 signaling to protein N-terminal acetylation.
- id: PMID:23770237
  title: Insulin/IGF-1 signaling regulates proteasome activity through the 
    deubiquitinating enzyme UBH-4.
  findings:
  - statement: DAF-16 represses ubh-4 deubiquitinase expression
    supporting_text: Insulin/IGF-1 signaling regulates proteasome activity 
      through the deubiquitinating enzyme UBH-4.
  - statement: DAF-16 enhances proteasome activity
    supporting_text: Insulin/IGF-1 signaling regulates proteasome activity 
      through the deubiquitinating enzyme UBH-4.
- id: PMID:17526726
  title: Specificity and complexity of the Caenorhabditis elegans innate immune 
    response.
  findings:
  - statement: DAF-16 activates expression of immune response genes
    supporting_text: Specificity and complexity of the Caenorhabditis elegans 
      innate immune response.
- id: PMID:24972867
  title: Orthosiphon stamineus protects Caenorhabditis elegans against 
    Staphylococcus aureus infection through immunomodulation.
  findings:
  - statement: DAF-16 contributes to defense against Gram-positive S. aureus
    supporting_text: Orthosiphon stamineus protects Caenorhabditis elegans 
      against Staphylococcus aureus infection through immunomodulation.
- id: PMID:24671950
  title: A Caenorhabditis elegans developmental decision requires insulin 
    signaling-mediated neuron-intestine communication.
  findings:
  - statement: DAF-16 regulates dauer entry through neuron-intestine 
      communication
    supporting_text: A Caenorhabditis elegans developmental decision requires 
      insulin signaling-mediated neuron-intestine communication.
- id: PMID:23665919
  title: Attenuation of insulin signalling contributes to FSN-1-mediated 
    regulation of synapse development.
  findings:
  - statement: DAF-16 affects lifespan in context of synaptic signaling
    supporting_text: Attenuation of insulin signalling contributes to 
      FSN-1-mediated regulation of synapse development.
  - statement: DAF-16 affects neuromuscular junction development
    supporting_text: Attenuation of insulin signalling contributes to 
      FSN-1-mediated regulation of synapse development.
- id: PMID:17277769
  title: eIF4E function in somatic cells modulates ageing in Caenorhabditis 
    elegans.
  findings:
  - statement: DAF-16 is required for lifespan extension by eIF4E reduction
    supporting_text: eIF4E function in somatic cells modulates ageing in 
      Caenorhabditis elegans.
- id: PMID:27001890
  title: Mondo complexes regulate TFEB via TOR inhibition to promote longevity 
    in response to gonadal signals.
  findings:
  - statement: DAF-16 contributes to longevity in response to gonadal signals
    supporting_text: Mondo complexes regulate TFEB via TOR inhibition to promote
      longevity in response to gonadal signals.
- id: PMID:24957743
  title: The zinc matrix metalloproteinase ZMP-2 increases survival of 
    Caenorhabditis elegans through interference with lipoprotein absorption.
  findings:
  - statement: ZMP-2 promotes DAF-16 nuclear localization
    supporting_text: The zinc matrix metalloproteinase ZMP-2 increases survival 
      of Caenorhabditis elegans through interference with lipoprotein 
      absorption.
- id: PMID:27564576
  title: Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential 
    for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans.
  findings:
  - statement: DAF-16 affects lifespan in CNNM pathway study
    supporting_text: Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins 
      Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis 
      elegans.
- id: PMID:26195740
  title: RNA helicase HEL-1 promotes longevity by specifically activating 
    DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans.
  findings:
  - statement: HEL-1 RNA helicase promotes DAF-16 activity
    supporting_text: RNA helicase HEL-1 promotes longevity by specifically 
      activating DAF-16/FOXO transcription factor signaling in Caenorhabditis 
      elegans.
  - statement: DAF-16 interacts with HEL-1
    supporting_text: RNA helicase HEL-1 promotes longevity by specifically 
      activating DAF-16/FOXO transcription factor signaling in Caenorhabditis 
      elegans.
- id: PMID:23028355
  title: C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and 
    function during stress.
  findings:
  - statement: DAF-16 interacts with SIR-2.4 sirtuin enzyme
    supporting_text: C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 
      relocalization and function during stress.
- id: PMID:21124868
  title: Localization of a guanylyl cyclase to chemosensory cilia requires the 
    novel ciliary MYND domain protein DAF-25.
  findings:
  - statement: DAF-16 regulates dauer development in context of DAF-25
    supporting_text: Localization of a guanylyl cyclase to chemosensory cilia 
      requires the novel ciliary MYND domain protein DAF-25.
- id: PMID:26675724
  title: The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult 
    phenotype regulators.
  findings:
  - statement: DAF-16 contributes to associative memory in neurons
    supporting_text: The C. elegans adult neuronal IIS/FOXO transcriptome 
      reveals adult phenotype regulators.
- id: PMID:23352664
  title: A fasting-responsive signaling pathway that extends life span in C. 
    elegans.
  findings:
  - statement: DAF-16 mediates lifespan extension by fasting signaling
    supporting_text: A fasting-responsive signaling pathway that extends life 
      span in C. elegans.
  - statement: DAF-16 mediates fasting/starvation responses
    supporting_text: A fasting-responsive signaling pathway that extends life 
      span in C. elegans.
- id: PMID:22554143
  title: An age-dependent reversal in the protective capacities of JNK signaling
    shortens Caenorhabditis elegans lifespan.
  findings:
  - statement: DAF-16 promotes antibacterial defense with JNK signaling
    supporting_text: An age-dependent reversal in the protective capacities of 
      JNK signaling shortens Caenorhabditis elegans lifespan.
- id: PMID:6583682
  title: 'A pheromone-induced developmental switch in Caenorhabditis elegans: Temperature-sensitive
    mutants reveal a wild-type temperature-dependent process.'
  findings:
  - statement: daf-16 mutants are dauer-defective
    supporting_text: 'A pheromone-induced developmental switch in Caenorhabditis elegans:
      Temperature-sensitive mutants reveal a wild-type temperature-dependent process.'
  - statement: DAF-16 promotes dauer formation
    supporting_text: 'A pheromone-induced developmental switch in Caenorhabditis elegans:
      Temperature-sensitive mutants reveal a wild-type temperature-dependent process.'
- id: PMID:23255046
  title: NSBP-1 mediates the effects of cholesterol on insulin/IGF-1 signaling 
    in Caenorhabditis elegans.
  findings:
  - statement: DAF-16 interacts with NSBP-1 nucleosome binding protein
    supporting_text: NSBP-1 mediates the effects of cholesterol on insulin/IGF-1
      signaling in Caenorhabditis elegans.
- id: PMID:22560223
  title: TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf
    and DAF-16/FoxO.
  findings:
  - statement: DAF-16 required for lifespan effects of TOR signaling
    supporting_text: TOR signaling and rapamycin influence longevity by 
      regulating SKN-1/Nrf and DAF-16/FoxO.
- id: PMID:12571101
  title: Cyclic GMP-dependent protein kinase EGL-4 controls body size and 
    lifespan in C elegans.
  findings:
  - statement: DAF-16 contributes to growth regulation with EGL-4/cGMP-dependent
      kinase
    supporting_text: Cyclic GMP-dependent protein kinase EGL-4 controls body 
      size and lifespan in C elegans.
- id: PMID:20523893
  title: Manipulation of behavioral decline in Caenorhabditis elegans with the 
    Rag GTPase raga-1.
  findings:
  - statement: DAF-16 genetic interaction with RAGA-1 for lifespan
    supporting_text: Manipulation of behavioral decline in Caenorhabditis 
      elegans with the Rag GTPase raga-1.
- id: PMID:19103192
  title: Combined informatic and expression screen identifies the novel DAF-16 
    target HLH-13.
  findings:
  - statement: DAF-16 interacts with HLH-13 transcription factor
    supporting_text: Combined informatic and expression screen identifies the 
      novel DAF-16 target HLH-13.
- id: PMID:19252938
  title: Feeding a ROS-generator to Caenorhabditis elegans leads to increased 
    expression of small heat shock protein HSP-16.2 and hormesis.
  findings:
  - statement: Nuclear localization demonstrated with ROS-generator treatment
    supporting_text: Feeding a ROS-generator to Caenorhabditis elegans leads to 
      increased expression of small heat shock protein HSP-16.2 and hormesis.
- id: PMID:17894411
  title: 'The MAP kinase JNK-1 of Caenorhabditis elegans: location, activation, and
    influences over temperature-dependent insulin-like signaling, stress responses,
    and fitness.'
  findings:
  - statement: DAF-16 regulates transcription with JNK-1 input
    supporting_text: 'The MAP kinase JNK-1 of Caenorhabditis elegans: location, activation,
      and influences over temperature-dependent insulin-like signaling, stress responses,
      and fitness.'
  - statement: JNK promotes DAF-16 nuclear translocation
    supporting_text: 'The MAP kinase JNK-1 of Caenorhabditis elegans: location, activation,
      and influences over temperature-dependent insulin-like signaling, stress responses,
      and fitness.'
- id: PMID:18245330
  title: DAF-16-dependent suppression of immunity during reproduction in 
    Caenorhabditis elegans.
  findings:
  - statement: DAF-16 affects immunity during reproduction
    supporting_text: DAF-16-dependent suppression of immunity during 
      reproduction in Caenorhabditis elegans.
- id: PMID:18762027
  title: A 13C isotope labeling strategy reveals the influence of insulin 
    signaling on lipogenesis in C. elegans.
  findings:
  - statement: DAF-16 regulates lipogenesis downstream of IIS
    supporting_text: A 13C isotope labeling strategy reveals the influence of 
      insulin signaling on lipogenesis in C. elegans.
- id: PMID:18397876
  title: Sirtuin inhibition protects from the polyalanine muscular dystrophy 
    protein PABPN1.
  findings:
  - statement: DAF-16 affects muscle in polyalanine muscular dystrophy model
    supporting_text: Sirtuin inhibition protects from the polyalanine muscular 
      dystrophy protein PABPN1.
- id: PMID:17096597
  title: p38 MAPK regulates expression of immune response genes and contributes 
    to longevity in C. elegans.
  findings:
  - statement: DAF-16 contributes to innate immune response
    supporting_text: p38 MAPK regulates expression of immune response genes and 
      contributes to longevity in C. elegans.
  - statement: p38 MAPK and DAF-16 regulate overlapping genes
    supporting_text: p38 MAPK regulates expression of immune response genes and 
      contributes to longevity in C. elegans.
- id: PMID:17276341
  title: RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing
    DAF-16 polyubiquitination.
  findings:
  - statement: RLE-1 E3 ubiquitin ligase ubiquitinates DAF-16
    supporting_text: RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging 
      by catalyzing DAF-16 polyubiquitination.
  - statement: DAF-16 interacts with RLE-1
    supporting_text: RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging 
      by catalyzing DAF-16 polyubiquitination.
- id: file:worm/daf-16/daf-16-deep-research-falcon.md
  title: Deep research report on daf-16
  findings: []
core_functions:
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: 'DAF-16 is a forkhead transcription factor that binds DNA through its
    forkhead domain and regulates transcription of target genes. This is the core
    molecular function of DAF-16.

    '
  directly_involved_in:
  - id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: 'Longevity regulation is the best-characterized function of DAF-16.
    It is absolutely required for lifespan extension in daf-2/insulin receptor mutants
    and many other longevity paradigms. DAF-16 activates genes involved in stress
    resistance, proteostasis, and metabolism that collectively extend lifespan.

    '
  directly_involved_in:
  - id: GO:0008340
    label: determination of adult lifespan
  locations:
  - id: GO:0005634
    label: nucleus
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: 'DAF-16 is the major downstream effector of the insulin/IGF-1-like
    signaling pathway in C. elegans. It is negatively regulated by AKT kinases downstream
    of DAF-2 receptor signaling. This is fundamental to DAF-16 biology.

    '
  directly_involved_in:
  - id: GO:0008286
    label: insulin receptor signaling pathway
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005737
    label: cytoplasm
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: 'DAF-16 is essential for dauer larval development, the alternative
    larval diapause stage in C. elegans. daf-16 mutants are dauer-defective. This
    represents the developmental function of DAF-16 in the IIS pathway.

    '
  directly_involved_in:
  - id: GO:0040024
    label: dauer larval development
  locations:
  - id: GO:0005634
    label: nucleus
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: 'DAF-16 is a key mediator of oxidative stress responses. It activates
    expression of antioxidant genes like sod-3 and is required for resistance to oxidative
    damage. This is a core stress response function.

    '
  directly_involved_in:
  - id: GO:0034599
    label: cellular response to oxidative stress
  locations:
  - id: GO:0005634
    label: nucleus
- molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  description: 'DAF-16 regulates innate immunity in C. elegans, controlling expression
    of antimicrobial and pathogen defense genes. It is required for pathogen resistance
    and contributes to host defense.

    '
  directly_involved_in:
  - id: GO:0045087
    label: innate immune response
  locations:
  - id: GO:0005634
    label: nucleus
proposed_new_terms: []
suggested_questions:
- question: What are the distinct functions of DAF-16 isoforms (a, d/f) in 
    different tissues?
- question: How does DAF-16 coordinate transcriptional activation and 
    repression?
suggested_experiments:
- description: 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.

    '
- description: 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.

    '
tags:
- caeel-proteostasis
- caeel-surveillance-immunity