id: Q8ITW8
gene_symbol: nhr-80
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  NHR-80 is a nuclear hormone receptor of the HNF4 family that functions as a
  ligand-activated transcription factor regulating fatty acid desaturation and
  longevity in C. elegans. NHR-80 directly binds oleoylethanolamide (OEA) with
  a Kd of approximately 7.8 uM, functioning as the nuclear receptor in a
  lysosome-to-nucleus retrograde lipid signaling pathway (LIPL-4 -> LBP-8 ->
  NHR-80). Its primary transcriptional targets are the delta-9 fatty acid
  desaturases fat-5, fat-6, and fat-7, with fat-7 being almost completely
  eliminated in nhr-80 mutants. NHR-80 physically interacts with NHR-49, which
  acts as a co-factor; together they activate transcription of desaturase genes
  and acs-2 (acyl-CoA synthetase for beta-oxidation). NHR-80 is essential for
  compensatory upregulation of fat-7 when fat-6 is lost, and fat-6;nhr-80
  double mutants are synthetically lethal due to insufficient desaturase
  activity. NHR-80 is specifically required for germline-mediated longevity
  (glp-1 pathway) but not for insulin/IIS, dietary restriction, or
  mitochondrial longevity pathways. Loss of nhr-80 does not substantially
  affect wild-type lifespan but completely abrogates glp-1 longevity, while
  overexpression extends glp-1 lifespan by 80% without affecting wild-type
  lifespan. NHR-80 is expressed in the intestine and some neurons, localizes
  constitutively to the nucleus, and is induced 5.6-fold in germline-less
  animals. NHR-80 also participates in citrate-induced mtUPR lipid metabolic
  responses and transgenerational lipid accumulation from high-fat diet.
alternative_products:
- name: b {ECO:0000312|WormBase:H10E21.3b}
  id: Q8ITW8-1
- name: a {ECO:0000312|WormBase:H10E21.3a}
  id: Q8ITW8-2
  sequence_note: VSP_061619
existing_annotations:
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-80 contains a zinc-finger DNA-binding domain (InterPro IPR049636,
      HNF4-like DBD) and functions as a transcription factor that directly
      regulates target gene promoters including fat-5, fat-6, fat-7, acs-2, and
      dgat-2 (PMID:16839188, PMID:25554789, PMID:35021096). The IEA annotation
      from InterPro is consistent with NHR-80 being a sequence-specific DNA
      binding transcription factor of the nuclear receptor family, although
      direct DNA binding to specific cis-regulatory sequences has not been
      demonstrated by in vitro assays.
    action: ACCEPT
    reason: >-
      NHR-80 is a nuclear hormone receptor with a conserved zinc-finger
      DNA-binding domain (HNF4-like). It regulates transcription of specific
      target genes including delta-9 desaturases, consistent with cis-regulatory
      region binding. The IEA annotation from InterPro domain mapping is
      appropriate for this NHR family member.
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        We found an RNAi clone, nhr-80, that caused C. elegans to accumulate
        increased levels of 18:0. NHR-80 is a member of the NHR family of
        transcription factors in C. elegans
    - reference_id: PMID:35021096
      supporting_text: >-
        NHR-80 then upregulates lipogenesis and lipid accumulation, shifting
        excess citrate for use in lipogenesis and for storage as
        triacylglycerol in lipid droplets
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        it is described as a **C4 zinc-finger nuclear receptor** (consistent with canonical NHR DNA-binding domains) and as an **HNF4-like NHR** in the context of germline-loss longevity.

- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-80 is a well-established transcription factor that regulates
      expression of multiple target genes including fat-5, fat-6, fat-7,
      acs-2, and dgat-2 (PMID:16839188, PMID:22511885, PMID:25554789,
      PMID:35021096). The InterPro-based IEA annotation is consistent with
      extensive experimental evidence. However, a more specific term such as
      ligand-activated transcription factor activity (GO:0098531) or nuclear
      receptor activity (GO:0004879) would better capture the function.
    action: MODIFY
    reason: >-
      While the annotation is correct, NHR-80 is specifically a
      ligand-activated nuclear receptor that binds oleoylethanolamide (OEA)
      with Kd ~7.8 uM (PMID:25554789). A more specific term would be more
      informative. GO:0098531 (ligand-activated transcription factor activity)
      or GO:0004879 (nuclear receptor activity) would better capture the
      molecular function.
    proposed_replacement_terms:
    - id: GO:0098531
      label: ligand-modulated transcription factor activity
    - id: GO:0004879
      label: nuclear receptor activity
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins,
        activated transcription of target genes of NHR-49 and NHR-80, and
        promoted longevity in C. elegans
    - reference_id: PMID:16839188
      supporting_text: >-
        NHR-80 is a member of the NHR family of transcription factors in C.
        elegans
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        the literature supports NHR-80 as a **lipid-state-responsive transcription factor** whose most reproducible functional output is **regulation of Δ9 desaturase programs** (fat-5/6/7) that tune MUFA/SFA balance.

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      NHR-80 nuclear localization has been directly demonstrated by IDA
      (PMID:21423649) and is also supported by UniProt subcellular location
      mapping. NHR-80::GFP is constitutively nuclear in intestinal cells and
      neurons. This IEA annotation is redundant with the IDA annotation below
      but is not wrong.
    action: ACCEPT
    reason: >-
      Correct annotation supported by direct experimental evidence from
      NHR-80::GFP localization studies (PMID:21423649) and consistent with
      NHR-80 being a nuclear receptor transcription factor.
    supported_by:
    - reference_id: PMID:21423649
      supporting_text: >-
        we found that NHR-80 is localized in the nucleus and that it is
        expressed in the intestine and in neurons
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        NHR-80 is reported as **expressed in the intestine** (major metabolic tissue) and shows **nuclear localization**, including increased intestinal nuclear signal in germline-less animals.

- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-80 regulates transcription of multiple target genes, particularly
      the delta-9 desaturases fat-5, fat-6, and fat-7, as well as acs-2 and
      dgat-2 (PMID:16839188, PMID:22511885, PMID:25554789, PMID:35021096).
      This broad IEA term is acceptable as a general annotation from InterPro
      domain mapping.
    action: ACCEPT
    reason: >-
      This is a broadly correct IEA annotation. NHR-80 is a transcription
      factor that regulates DNA-templated transcription. While more specific
      terms exist (positive regulation of transcription by RNA polymerase II
      is also annotated), this general term from InterPro mapping is not wrong
      and captures the core transcriptional regulatory function.
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        Gene expression by QPCR in the nhr-80 mutant reveals a decrease in
        expression of the Δ9 desaturase genes relative to wild type
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        the best-supported primary function is that **NHR-80 is a transcriptional regulator of fatty-acid desaturation and lipogenic remodeling**, particularly maintaining sufficient **monounsaturated fatty acids (MUFAs)** by regulating **Δ9 desaturases**.

- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-80 contains two C4-type zinc finger motifs in its DNA-binding
      domain (residues 30-50 and 66-86 per UniProt feature annotations).
      These are conserved NR C4-type zinc fingers that coordinate zinc ions
      for DNA binding. The InterPro-based IEA annotation is structurally
      well-supported.
    action: ACCEPT
    reason: >-
      NHR-80 has two NR C4-type zinc finger motifs in its DNA-binding domain
      that require zinc ion coordination for proper folding and DNA binding.
      This is a standard structural feature of all nuclear hormone receptors
      and is well supported by sequence analysis.
    supported_by:
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        it is described as a **C4 zinc-finger nuclear receptor** (consistent with canonical NHR DNA-binding domains) and as an **HNF4-like NHR** in the context of germline-loss longevity.

- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-80 contains a conserved HNF4-like DNA-binding domain (CDD:cd06960
      NR_DBD_HNF4A) and functions as a transcription factor that selectively
      regulates specific target genes. The IEA annotation from InterPro is
      consistent with domain architecture, though direct DNA binding to
      specific sequences has not been demonstrated by in vitro assays.
    action: ACCEPT
    reason: >-
      Appropriate IEA annotation based on the conserved nuclear receptor
      DNA-binding domain. NHR-80 clearly binds specific regulatory elements
      to control target gene expression, as demonstrated by its selective
      regulation of fat-5, fat-6, fat-7 and other target genes.
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        NHR-80 is a member of the NHR family of transcription factors in C.
        elegans

- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:22511885
  review:
    summary: >-
      PMID:22511885 (Pathare et al. 2012) performed genome-wide microarray
      analysis on nhr-80 mutants and found that NHR-80 regulates genes
      involved in several processes including embryonic development and cell
      death. Some genes were upregulated in nhr-80 mutants, consistent with
      NHR-80 repressing their transcription. However, the primary and
      best-characterized function of NHR-80 is as a transcriptional
      activator of fatty acid desaturase genes (fat-5, fat-6, fat-7). The
      paper's model explicitly states that "NHR-49 binds to NHR-80 to
      activate the fatty acid desaturase genes." Negative regulation of some
      genes may occur but it is not the primary or best-characterized
      function of NHR-80.
    action: KEEP_AS_NON_CORE
    reason: >-
      The genome-wide microarray of nhr-80 mutants identified an NHR-80
      target set regulated independently of NHR-49, including genes involved
      in embryonic development and cell death; some of these targets are
      derepressed (upregulated) when NHR-80 is lost, consistent with NHR-80
      acting as a repressor for a subset of genes (PMID:22511885). However,
      NHR-80 is overwhelmingly characterized in the literature as a positive
      transcriptional regulator: its best-characterized output is activation
      of the delta-9 desaturase genes, where the model is that "NHR-49 binds
      to NHR-80 to activate the fatty acid desaturase genes." Negative
      regulation is therefore a secondary, less-characterized function rather
      than the core role, so the annotation is retained as non-core.
    supported_by:
    - reference_id: PMID:22511885
      supporting_text: >-
        The NHR-80 GO analysis indicates that it regulates genes involved in
        several different processes including embryonic development and cell
        death
    - reference_id: PMID:22511885
      supporting_text: >-
        we performed a genome-wide microarray analysis on nhr-66 and nhr-80
        mutants

- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:22511885
  review:
    summary: >-
      NHR-80 is a central regulator of lipid metabolism in C. elegans. Loss
      of nhr-80 causes accumulation of 18:0 saturated fatty acid and
      reduction of 18:1delta9 monounsaturated fatty acid (PMID:16839188).
      NHR-80 regulates expression of delta-9 desaturases (fat-5, fat-6,
      fat-7) that are key enzymes in fatty acid desaturation
      (PMID:16839188, PMID:22511885). NHR-80 also regulates dgat-2 for
      lipid storage and acs-2 for beta-oxidation (PMID:35021096,
      PMID:25554789). This is a core function.
    action: ACCEPT
    reason: >-
      Lipid metabolism is the primary function of NHR-80. Multiple studies
      demonstrate its role in regulating fatty acid composition, desaturase
      gene expression, and lipid homeostasis. This broad BP term appropriately
      captures the core biological role.
    supported_by:
    - reference_id: PMID:22511885
      supporting_text: >-
        nhr-80 and nhr-13 deletion mutants do not affect the sphingolipid,
        lipid remodeling, or β-oxidation genes. Instead, these mutants
        exhibited a decreased expression of the fatty acid desaturase genes
        fat-7, fat-5 and fat-6
    - reference_id: PMID:16839188
      supporting_text: >-
        the nhr-80 mutants, 18:0 accounts for about 10.2 ± 0.3% of the
        total fatty acids and 18:1 Δ9 accounts for 2.2 ± 0.1%, as compared
        with 6.8 ± 0.2% and 3.2 ± 0.1%, respectively, in the wild type
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        In **nhr-80(tm1011)** mutants, **stearic acid (18:0)** increases and **oleic acid (18:1 Δ9)** decreases compared to wild type; importantly, **triglyceride fraction is unchanged**, consistent with a role in composition/homeostasis rather than bulk storage under baseline conditions.

- term:
    id: GO:0009791
    label: post-embryonic development
  evidence_type: IGI
  original_reference_id: PMID:16839188
  review:
    summary: >-
      The IGI annotation with WB:WBGene00001398 (fat-6) reflects the
      synthetic lethality between nhr-80 and fat-6: fat-6;nhr-80 double
      mutants become thin, slow growing, and reproductively inviable after
      4 days (PMID:16839188). This represents a genetic interaction effect
      on post-embryonic viability rather than a primary developmental role
      for NHR-80. The nhr-80 single mutant is viable and fertile with no
      obvious post-embryonic developmental defects.
    action: KEEP_AS_NON_CORE
    reason: >-
      The post-embryonic development annotation reflects the fat-6;nhr-80
      synthetic lethality phenotype rather than a primary developmental
      function of NHR-80 alone. The nhr-80 single mutant shows no
      significant developmental defects. This is a secondary consequence of
      insufficient desaturase activity in the double mutant context, not a
      core function of NHR-80.
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        The fat-6 mutants, when grown on nhr-80(RNAi) from eggs, become
        thin, slow growing, and reproductively inviable after 4 d of growth
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        **fat-6;nhr-80** double deficiency (or fat-6 with nhr-80 RNAi) results in severe growth/viability defects on unsupplemented plates, and the compensatory induction of other desaturases (e.g., fat-7) requires NHR-80.

- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:27001890
  review:
    summary: >-
      PMID:27001890 (Nakamura et al. 2016) identified Mondo complexes
      (MML-1/MXL-2) as regulators of germline-mediated longevity. The paper
      mentions NHR-80/HNF4 as one of "virtually every known longevity
      factor" required for the gonadal longevity pathway, citing prior work.
      The IGI annotation with WB:WBGene00001609 (glp-1) reflects the genetic
      interaction between nhr-80 and glp-1 in lifespan determination. This
      is well-supported by extensive data from PMID:21423649 (Goudeau 2011)
      showing that nhr-80 is specifically required for glp-1-mediated
      longevity but does not affect wild-type lifespan. NHR-80 loss
      completely abrogates glp-1 longevity, and NHR-80 overexpression
      extends glp-1 lifespan by 80%.
    action: ACCEPT
    reason: >-
      NHR-80 is a well-established regulator of germline-mediated longevity.
      Loss of nhr-80 completely suppresses the lifespan extension in
      germline-less glp-1 mutants (PMID:21423649). The LIPL-4/LBP-8/NHR-80
      lysosome-to-nucleus signaling pathway is a major longevity mechanism
      (PMID:25554789). While NHR-80 does not affect wild-type lifespan, its
      role in lifespan determination in the germline-less context is a key
      biological function.
    additional_reference_ids:
    - PMID:21423649
    - PMID:25554789
    supported_by:
    - reference_id: PMID:27001890
      supporting_text: >-
        Virtually, every known longevity factor including the steroid
        receptor DAF-12/FXR, DAF-16/FOXO, HSF-1, NHR-80/HNF4, PHA-4/FOXA
        and NHR-49/PPARα function in this pathway
    - reference_id: PMID:21423649
      supporting_text: >-
        nhr-80/HNF4 is induced in animals lacking a germ line and is
        specifically required for their extended longevity
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        nhr-80 is selectively required for this longevity program: loss of nhr-80 reduces mean lifespan of glp-1 germline-less animals by **45% (p < 0.0001)** while having no significant effect on WT lifespan

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21423649
  review:
    summary: >-
      Goudeau et al. (2011) directly demonstrated nuclear localization of
      NHR-80 using a functional NHR-80::GFP translational fusion driven by
      its own promoter. NHR-80::GFP is constitutively nuclear in both
      intestinal cells and neurons, regardless of germline status. The
      intensity of NHR-80::GFP in intestinal nuclei increases 1.6-fold in
      germline-less (glp-1) animals (PMID:21423649).
    action: ACCEPT
    reason: >-
      Direct experimental evidence (IDA) from NHR-80::GFP translational
      fusion shows constitutive nuclear localization in intestinal cells and
      neurons. This is consistent with NHR-80 being a nuclear receptor
      transcription factor.
    supported_by:
    - reference_id: PMID:21423649
      supporting_text: >-
        we found that NHR-80 is localized in the nucleus and that it is
        expressed in the intestine and in neurons (some head and tail
        neurons, as well as the ventral cord
    - reference_id: PMID:21423649
      supporting_text: >-
        We found that NHR-80 nuclear localization is constitutive and
        independent of the presence of the germ line
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        The paper provides direct imaging evidence of intestinal nuclear localization of **NHR-80::GFP** in germline-depleted contexts

- term:
    id: GO:0045923
    label: positive regulation of fatty acid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:16839188
  review:
    summary: >-
      NHR-80 positively regulates expression of delta-9 desaturases fat-5,
      fat-6, and fat-7. Loss of nhr-80 reduces fat-5 expression by 66%,
      fat-6 by 22%, and almost completely eliminates fat-7 expression
      (PMID:16839188). NHR-80 is specifically required for compensatory
      upregulation of fat-7 when fat-6 is lost. The nhr-80 mutant shows
      accumulation of 18:0 saturated fatty acid and reduced 18:1delta9,
      consistent with reduced desaturase activity. This annotation
      accurately captures NHR-80's role as a positive regulator of fatty
      acid desaturation.
    action: ACCEPT
    reason: >-
      This is a core function of NHR-80. Multiple studies demonstrate that
      NHR-80 positively regulates fatty acid metabolism by activating
      transcription of delta-9 desaturase genes. The IMP evidence from
      nhr-80 mutant phenotype (altered fatty acid composition) directly
      supports this annotation.
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        On average, fat-5 and fat-6 expression were reduced by 66% and 22%
        respectively, while fat-7 expression was almost completely eliminated
        in the nhr-80 mutants
    - reference_id: PMID:16839188
      supporting_text: >-
        NHR-80 is required for increasing fat-7 expression in situations
        where higher fat-7 levels are necessary and consequently defines a
        critical regulator of fatty acid metabolism
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        In fat-6 mutants, fat-7 can increase **~37-fold**, but under **nhr-80 RNAi fat-7 expression falls to <10%** of fat-6 control levels.

- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:16839188
  review:
    summary: >-
      NHR-80 positively regulates transcription of delta-9 desaturase genes
      fat-5, fat-6, and fat-7 as shown by qRT-PCR and GFP reporter analysis
      in nhr-80 mutants and nhr-80(RNAi) animals (PMID:16839188). NHR-80
      also activates transcription of acs-2 via the LIPL-4/LBP-8 signaling
      pathway (PMID:25554789) and dgat-2 (PMID:35021096). The model from
      PMID:22511885 explicitly places NHR-80 as an activator: "NHR-49 binds
      to NHR-80 to activate the fatty acid desaturase genes."
    action: ACCEPT
    reason: >-
      Positive regulation of transcription by RNA polymerase II is the
      primary molecular mechanism by which NHR-80 exerts its biological
      functions. This is supported by extensive evidence from multiple
      studies showing reduced target gene expression in nhr-80 mutants and
      RNAi knockdowns.
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        Expression of fat-7 whole gene::GFP was completely eliminated by the
        RNAi treatment. Expression of fat-5 promoter::GFP was decreased but
        only in the intestine
    - reference_id: PMID:22511885
      supporting_text: >-
        NHR-49 (blue) binds to NHR-80 (green) to activate the fatty acid
        desaturase genes
    - reference_id: PMID:25554789
      supporting_text: >-
        acs-2 transcription was increased more than 15-fold in lipl-4 Tg
        animals; this effect was dependent on nhr-49 and nhr-80
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        NHR-80 then binds/transactivates lipogenic genes including **dgat-2** and desaturases. This connects mitochondrial surveillance to lipid storage/remodeling programs.

- term:
    id: GO:0098531
    label: ligand-modulated transcription factor activity
  evidence_type: IDA
  original_reference_id: PMID:25554789
  review:
    summary: >-
      Folick et al. (2015) demonstrated that oleoylethanolamide (OEA)
      directly binds to NHR-80 protein. OEA treatment activates transcription
      of lbp-8 and acs-2 in an nhr-80-dependent manner. This establishes
      NHR-80 as a ligand-activated transcription factor with OEA as its
      direct ligand. This annotation is not currently in GOA but represents
      a key molecular function.
    action: NEW
    reason: >-
      NHR-80 has been shown to directly bind OEA and activate transcription
      of target genes in response to this lipid signal. This is a more
      specific and informative MF annotation than the generic DNA-binding
      transcription factor activity currently annotated. The evidence from
      PMID:25554789 clearly supports ligand-activated transcription factor
      activity as a core molecular function.
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins,
        activated transcription of target genes of NHR-49 and NHR-80, and
        promoted longevity in C. elegans
    - reference_id: PMID:25554789
      supporting_text: >-
        After 3 hours treatment with OEA analogue, transcription of lbp-8
        and acs-2 was increased more than 4- and 7-fold above the control
        levels, respectively
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        metabolomics identified **oleoylethanolamide (OEA)** as a lipid increased by LIPL-4 that **binds LBP-8 and NHR-80** and activates NHR-49/NHR-80 target transcription.

- term:
    id: GO:0016922
    label: nuclear receptor binding
  evidence_type: IPI
  original_reference_id: PMID:22511885
  review:
    summary: >-
      NHR-80 physically interacts with NHR-49 as demonstrated by yeast
      two-hybrid and in vitro GST pull-down assays (PMID:22511885). This
      interaction is essential for coordinate transcriptional activation of
      delta-9 fatty acid desaturase genes (fat-5, fat-6, fat-7). NHR-80
      heterodimerizes with NHR-49, a distinct nuclear receptor, so nuclear
      receptor binding is the specific and accurate term for this
      interaction; NHR-80 has not been shown to homodimerize.
    action: NEW
    reason: >-
      NHR-80 directly binds NHR-49, a nuclear hormone receptor, as
      demonstrated by GST pull-down assays. This specific nuclear receptor
      binding activity is functionally essential for desaturase gene
      regulation and is more informative than generic protein binding terms.
    supported_by:
    - reference_id: PMID:22511885
      supporting_text: >-
        In addition, it was also able to interact directly with NHR-66 and
        NHR-80
    - reference_id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
      supporting_text: |-
        NHR-80 serves as a **binding partner/cofactor of NHR-49**, and the pair regulates subsets of lipid-metabolism genes—especially desaturases.

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings:
  - statement: InterPro domains IPR049636 (HNF4-like DBD), IPR001628 (Znf_hrmn_rcpt),
      and IPR013088 (Znf_NHR/GATA) map NHR-80 to transcription factor and zinc ion
      binding GO terms.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings:
  - statement: UniProt subcellular location maps NHR-80 to nucleus, consistent with
      experimental data from NHR-80 GFP localization studies.
- id: PMID:16839188
  title: Genetic regulation of unsaturated fatty acid composition in C. elegans.
  findings:
  - statement: Identified NHR-80 as a novel nuclear hormone receptor that regulates
      delta-9 desaturase gene expression (fat-5, fat-6, fat-7) in C. elegans.
    supporting_text: >-
      We found an RNAi clone, nhr-80, that caused C. elegans to accumulate
      increased levels of 18:0. NHR-80 is a member of the NHR family of
      transcription factors in C. elegans
  - statement: nhr-80 mutants accumulate 18:0 (10.2%) and have reduced 18:1delta9
      (2.2%) compared to wild type (6.8% and 3.2% respectively).
    supporting_text: >-
      In the nhr-80 mutants, 18:0 accounts for about 10.2 ± 0.3% of the
      total fatty acids and 18:1 Δ9 accounts for 2.2 ± 0.1%, as compared
      with 6.8 ± 0.2% and 3.2 ± 0.1%, respectively, in the wild type
  - statement: fat-7 expression is almost completely eliminated in nhr-80 mutants;
      fat-5 reduced 66%; fat-6 reduced 22%.
    supporting_text: >-
      On average, fat-5 and fat-6 expression were reduced by 66% and 22%
      respectively, while fat-7 expression was almost completely eliminated
      in the nhr-80 mutants
  - statement: NHR-80 is required for compensatory upregulation of fat-7 when fat-6
      is lost. fat-6;nhr-80 double mutants are synthetically lethal.
    supporting_text: >-
      The fat-6 mutants, when grown on nhr-80(RNAi) from eggs, become
      thin, slow growing, and reproductively inviable after 4 d of growth
  - statement: nhr-80 mutants have a slightly shorter lifespan (~10%) than wild type
      but much longer than nhr-49 mutants.
    supporting_text: >-
      the average lifespan of the nhr-80 mutant was 12.5 ± 0.5 d as
      compared to 13.9 ± 0.4 d in wild-type animals and 8.2 ± 0.2 d in
      nhr-49 mutants when grown at 25 °C
- id: PMID:21423649
  title: Fatty acid desaturation links germ cell loss to longevity through NHR-80/HNF4
    in C. elegans.
  findings:
  - statement: NHR-80 is specifically required for germline-mediated longevity but
      not for daf-2, dietary restriction, or mitochondrial longevity pathways.
    supporting_text: >-
      nhr-80/HNF4 is induced in animals lacking a germ line and is
      specifically required for their extended longevity
  - statement: NHR-80::GFP localizes constitutively to nuclei in intestine and neurons;
      intensity increases 1.6-fold in germline-less animals.
    supporting_text: >-
      we found that NHR-80 is localized in the nucleus and that it is
      expressed in the intestine and in neurons (some head and tail
      neurons, as well as the ventral cord
  - statement: nhr-80 mRNA is induced 5.6-fold in glp-1(e2141ts) mutant animals.
    supporting_text: >-
      nhr-80 mRNA levels are increased in glp-1(e2141ts) mutants as
      measured by qRT-PCR (5.6-fold increase; Wilcoxon rank-sum test p
      value <0.05 when compared with N2)
  - statement: NHR-80 overexpression extends glp-1 lifespan by 80% but does not extend
      wild-type lifespan.
    supporting_text: >-
      Surprisingly, the nhr-80 transgene, which fully restores the
      longevity of glp-1(e2141ts);nhr-80(tm1011) mutant animals (Figure
      S3, Table S1), fails to extend the lifespan of wild type animals
      (Figure 4A, Table S1) but increases the mean lifespan of
      glp-1(e2141ts) mutant animals by 80% (Figure 4B, Table S1)
  - statement: NHR-80 functions independently of DAF-16 but requires DAF-12 for longevity.
    supporting_text: >-
      overexpressing nhr-80 increases lifespan by 40% ... while nhr-80
      RNAi decreases lifespan by 58% ... Thus, DAF-16 is not strictly
      required for nhr-80 function
  - statement: fat-6 is a key NHR-80 target in the germline-less longevity context.
    supporting_text: >-
      fat-6 Is Induced in glp-1(e2141ts) Mutant Animals in a NHR-80
      Dependent Manner
- id: PMID:22511885
  title: Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships.
  findings:
  - statement: NHR-49 and NHR-80 physically interact directly, as shown by yeast two-hybrid
      and in vitro GST pull-down assays.
    supporting_text: >-
      it was also able to interact directly with NHR-66 and NHR-80
  - statement: NHR-49/NHR-80 partnership activates desaturase genes; NHR-49/NHR-66
      partnership represses sphingolipid genes.
    supporting_text: >-
      NHR-49 (blue) binds to NHR-80 (green) to activate the fatty acid
      desaturase genes
  - statement: nhr-80 mutants show reduced expression of fat-5, fat-6, and fat-7 but
      do not affect sphingolipid, lipid remodeling, or beta-oxidation genes.
    supporting_text: >-
      nhr-80 and nhr-13 deletion mutants do not affect the sphingolipid,
      lipid remodeling, or β-oxidation genes. Instead, these mutants
      exhibited a decreased expression of the fatty acid desaturase genes
      fat-7, fat-5 and fat-6
  - statement: nhr-80;nhr-13 double mutants have lifespan approaching nhr-49 mutants,
      with C18:0/C18:1n9 ratio correlated to lifespan.
    supporting_text: >-
      an nhr-80; nhr-13 double mutant had a lifespan of 12.29+/−0.37
      days, which approaches the nhr-49 mutant lifespan of 9.52+/−0.23
      days
  - statement: nhr-80 mutants show abnormal mitochondrial morphology.
    supporting_text: >-
      nhr-49, nhr-66, and nhr-80 animals have abnormal mitochondrial
      phenotypes
- id: PMID:25554789
  title: Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis
    elegans.
  findings:
  - statement: OEA directly binds to NHR-80 protein and activates transcription of
      NHR-49/NHR-80 target genes.
    supporting_text: >-
      oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins,
      activated transcription of target genes of NHR-49 and NHR-80, and
      promoted longevity in C. elegans
  - statement: NHR-80 is required for LIPL-4 and LBP-8 mediated longevity extension.
    supporting_text: >-
      The loss-of-function mutation nhr-80(tm1011) abrogated longevity
      extension without affecting the lifespan of WT worms
  - statement: acs-2 transcription is increased more than 15-fold in lipl-4 Tg animals
      in an nhr-49 and nhr-80 dependent manner.
    supporting_text: >-
      acs-2 transcription was increased more than 15-fold in lipl-4 Tg
      animals; this effect was dependent on nhr-49 and nhr-80
  - statement: OEA analogue treatment increases transcription of lbp-8 (4-fold) and
      acs-2 (7-fold), abrogated in nhr-80(tm1011) mutant.
    supporting_text: >-
      After 3 hours treatment with OEA analogue, transcription of lbp-8
      and acs-2 was increased more than 4- and 7-fold above the control
      levels, respectively
- id: PMID:27001890
  title: Mondo complexes regulate TFEB via TOR inhibition to promote longevity in
    response to gonadal signals.
  findings:
  - statement: NHR-80/HNF4 is listed among the known longevity factors required for
      the gonadal longevity pathway, along with DAF-12, DAF-16, HSF-1, PHA-4, and
      NHR-49.
    supporting_text: >-
      Virtually, every known longevity factor including the steroid
      receptor DAF-12/FXR, DAF-16/FOXO, HSF-1, NHR-80/HNF4, PHA-4/FOXA
      and NHR-49/PPARα function in this pathway
  - statement: MML-1/MXL-2 Mondo complexes are required for germline-mediated longevity
      and regulate HLH-30/TFEB nuclear localization via TOR inhibition.
    supporting_text: >-
      mml-1 and mxl-2 deletions abolished lifespan extension in glp-1
      mutants and in animals whose germline precursors were removed by
      laser microsurgery
- id: PMID:35021096
  title: NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid
    accumulation in Caenorhabditis elegans.
  findings:
  - statement: NHR-80 functions in citrate-induced mtUPR to regulate lipid metabolism
      by binding to regulatory elements and regulating transcription of target genes
      including dgat-2.
- id: PMID:35140229
  title: Histone H3K4me3 modification is a transgenerational epigenetic signal for
    lipid metabolism in Caenorhabditis elegans.
  findings:
  - statement: NHR-80 is required for transgenerational lipid accumulation in response
      to high-fat diet in C. elegans.
- id: file:worm/nhr-80/nhr-80-deep-research-falcon.md
  title: Falcon deep research report on C. elegans nhr-80 (UniProt Q8ITW8)
  findings:
  - statement: |-
      Falcon synthesis confirms NHR-80 as an HNF4-like / C4 zinc-finger nuclear hormone
      receptor whose most reproducible function is transcriptional regulation of Δ9
      desaturase programs (fat-5/fat-6/fat-7) that tune the MUFA/SFA balance, deployed in
      homeostasis, desaturation-stress compensation, longevity, and starvation development.
    reference_section_type: OTHER
    supporting_text: |-
      the literature supports NHR-80 as a **lipid-state-responsive transcription factor** whose most reproducible functional output is **regulation of Δ9 desaturase programs** (fat-5/6/7) that tune MUFA/SFA balance.
  - statement: |-
      Falcon corroborates the NHR-80/NHR-49 partnership as a central node in lipid
      homeostasis, with NHR-80 acting as a binding partner/cofactor of NHR-49 to activate
      desaturase gene expression.
    reference_section_type: OTHER
    supporting_text: |-
      NHR-80 physically and functionally partners with **NHR-49** to activate fatty-acid desaturase genes; this partnership is a central node in lipid-homeostasis regulation.
  - statement: |-
      Falcon highlights oleoylethanolamide (OEA) as the strongest direct metabolite/ligand
      evidence: increased by LIPL-4 lysosomal signaling, OEA binds LBP-8 and NHR-80 and
      activates NHR-49/NHR-80 target transcription, supporting ligand-modulated
      transcription factor activity.
    reference_section_type: OTHER
    supporting_text: |-
      metabolomics identified **oleoylethanolamide (OEA)** as a lipid increased by LIPL-4 that **binds LBP-8 and NHR-80** and activates NHR-49/NHR-80 target transcription.
  - statement: |-
      Falcon notes NHR-80 is induced under the mitochondrial UPR (downstream of DVE-1) and
      then binds/transactivates lipogenic genes including dgat-2 and desaturases, linking
      mitochondrial surveillance to lipid storage/remodeling.
    reference_section_type: OTHER
    supporting_text: |-
      NHR-80 then binds/transactivates lipogenic genes including **dgat-2** and desaturases. This connects mitochondrial surveillance to lipid storage/remodeling programs.
core_functions:
- description: >-
    OEA-activated nuclear receptor transcription factor that directly binds
    oleoylethanolamide (OEA) and activates transcription of lipid metabolism
    target genes (fat-5, fat-6, fat-7, acs-2, dgat-2) as part of the
    LIPL-4/LBP-8/NHR-80 lysosome-to-nucleus signaling pathway
  molecular_function:
    id: GO:0098531
    label: ligand-modulated transcription factor activity
  directly_involved_in:
  - id: GO:0045923
    label: positive regulation of fatty acid metabolic process
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:25554789
    supporting_text: >-
      oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins,
      activated transcription of target genes of NHR-49 and NHR-80, and
      promoted longevity in C. elegans
  - reference_id: PMID:16839188
    supporting_text: >-
      fat-5 and fat-6 expression were reduced by 66% and 22% respectively,
      while fat-7 expression was almost completely eliminated in the nhr-80
      mutants
  - reference_id: PMID:22511885
    supporting_text: >-
      Although HNF4 is not yet known to dimerize with other partners, it will be critical
      to determine if there are similar cofactors and/or it carries out similar mechanistic
      roles.10.1371/journal.pgen.1002645.g009Figure 9Model of NHR-49–dependent regulation
      of lipid metabolism.We propose that NHR-49 (blue) interacts with NHR-66 (pink)
      to repress genes involved in sphingolipid processing and lipid remodeling, whereas
      NHR-49 (blue) binds to NHR-80 (green) to activate the fatty acid desaturase
      genes.Another interesting finding of this study is the complexity of the NHR-49
      regulatory network
- description: >-
    NHR-80 physically interacts with NHR-49 to form a heterodimeric nuclear
    receptor partnership that coordinately activates transcription of delta-9
    fatty acid desaturase genes (fat-5, fat-6, fat-7) and beta-oxidation
    genes (acs-2), maintaining proper monounsaturated fatty acid levels
  molecular_function:
    id: GO:0016922
    label: nuclear receptor binding
  directly_involved_in:
  - id: GO:0006629
    label: lipid metabolic process
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:22511885
    supporting_text: >-
      In addition, it was also able to interact directly with NHR-66 and
      NHR-80
  - reference_id: PMID:22511885
    supporting_text: >-
      nhr-80 and nhr-13 deletion mutants do not affect the sphingolipid,
      lipid remodeling, or beta-oxidation genes. Instead, these mutants
      exhibited a decreased expression of the fatty acid desaturase genes
      fat-7, fat-5 and fat-6
- description: >-
    NHR-80 is specifically required for lifespan extension in germline-less
    animals (glp-1 pathway), linking fatty acid desaturation to longevity
    signaling; nhr-80 loss completely abrogates glp-1 longevity while
    overexpression extends glp-1 lifespan by 80%
  molecular_function:
    id: GO:0098531
    label: ligand-modulated transcription factor activity
  directly_involved_in:
  - id: GO:0008340
    label: determination of adult lifespan
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:21423649
    supporting_text: >-
      nhr-80/HNF4 is induced in animals lacking a germ line and is
      specifically required for their extended longevity
  - reference_id: PMID:25554789
    supporting_text: >-
      The loss-of-function mutation nhr-80(tm1011) abrogated longevity
      extension without affecting the lifespan of WT worms