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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:16839188 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 PMID:35021096 NHR-80 then upregulates lipogenesis and lipid accumulation, shifting excess citrate for use in lipogenesis and for storage as triacylglycerol in lipid droplets file:worm/nhr-80/nhr-80-deep-research-falcon.md 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. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | MODIFY | 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. 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 replacements: ligand-modulated transcription factor activity nuclear receptor activity Supporting Evidence: PMID:25554789 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 PMID:16839188 NHR-80 is a member of the NHR family of transcription factors in C. elegans file:worm/nhr-80/nhr-80-deep-research-falcon.md the literature supports NHR-80 as a **lipid-state-responsive transcription factor** whose most reproducible functional output is **regulation of Ξ9 desaturase programs** (fat-5/6/7) that tune MUFA/SFA balance. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | 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. 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. Supporting Evidence: PMID:21423649 we found that NHR-80 is localized in the nucleus and that it is expressed in the intestine and in neurons file:worm/nhr-80/nhr-80-deep-research-falcon.md 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. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:16839188 Gene expression by QPCR in the nhr-80 mutant reveals a decrease in expression of the Ξ9 desaturase genes relative to wild type file:worm/nhr-80/nhr-80-deep-research-falcon.md 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 **Ξ9 desaturases**. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: file:worm/nhr-80/nhr-80-deep-research-falcon.md 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. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:16839188 NHR-80 is a member of the NHR family of transcription factors in C. elegans |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:22511885 Coordinate regulation of lipid metabolism by novel nuclear r... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:22511885 The NHR-80 GO analysis indicates that it regulates genes involved in several different processes including embryonic development and cell death PMID:22511885 we performed a genome-wide microarray analysis on nhr-66 and nhr-80 mutants |
| GO:0006629 lipid metabolic process | IMP PMID:22511885 Coordinate regulation of lipid metabolism by novel nuclear r... | ACCEPT | 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. 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. Supporting Evidence: PMID:22511885 nhr-80 and nhr-13 deletion mutants do not affect the sphingolipid, lipid remodeling, or Ξ²-oxidation genes. Instead, these mutants exhibited a decreased expression of the fatty acid desaturase genes fat-7, fat-5 and fat-6 PMID:16839188 the nhr-80 mutants, 18:0 accounts for about 10.2 Β± 0.3% of the total fatty acids and 18:1 Ξ9 accounts for 2.2 Β± 0.1%, as compared with 6.8 Β± 0.2% and 3.2 Β± 0.1%, respectively, in the wild type file:worm/nhr-80/nhr-80-deep-research-falcon.md In **nhr-80(tm1011)** mutants, **stearic acid (18:0)** increases and **oleic acid (18:1 Ξ9)** decreases compared to wild type; importantly, **triglyceride fraction is unchanged**, consistent with a role in composition/homeostasis rather than bulk storage under baseline conditions. |
| GO:0009791 post-embryonic development | IGI PMID:16839188 Genetic regulation of unsaturated fatty acid composition in ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:16839188 The fat-6 mutants, when grown on nhr-80(RNAi) from eggs, become thin, slow growing, and reproductively inviable after 4 d of growth file:worm/nhr-80/nhr-80-deep-research-falcon.md **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. |
| GO:0008340 determination of adult lifespan | IGI PMID:27001890 Mondo complexes regulate TFEB via TOR inhibition to promote ... | ACCEPT | 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%. 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. Supporting Evidence: PMID:27001890 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/PPARΞ± function in this pathway PMID:21423649 nhr-80/HNF4 is induced in animals lacking a germ line and is specifically required for their extended longevity file:worm/nhr-80/nhr-80-deep-research-falcon.md 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 |
| GO:0005634 nucleus | IDA PMID:21423649 Fatty acid desaturation links germ cell loss to longevity th... | ACCEPT | 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). 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. Supporting Evidence: PMID:21423649 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 PMID:21423649 We found that NHR-80 nuclear localization is constitutive and independent of the presence of the germ line file:worm/nhr-80/nhr-80-deep-research-falcon.md The paper provides direct imaging evidence of intestinal nuclear localization of **NHR-80::GFP** in germline-depleted contexts |
| GO:0045923 positive regulation of fatty acid metabolic process | IMP PMID:16839188 Genetic regulation of unsaturated fatty acid composition in ... | ACCEPT | 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. 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. Supporting Evidence: PMID:16839188 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 PMID:16839188 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 file:worm/nhr-80/nhr-80-deep-research-falcon.md 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. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:16839188 Genetic regulation of unsaturated fatty acid composition in ... | ACCEPT | 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." 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. Supporting Evidence: PMID:16839188 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 PMID:22511885 NHR-49 (blue) binds to NHR-80 (green) to activate the fatty acid desaturase genes PMID:25554789 acs-2 transcription was increased more than 15-fold in lipl-4 Tg animals; this effect was dependent on nhr-49 and nhr-80 file:worm/nhr-80/nhr-80-deep-research-falcon.md NHR-80 then binds/transactivates lipogenic genes including **dgat-2** and desaturases. This connects mitochondrial surveillance to lipid storage/remodeling programs. |
| GO:0098531 ligand-modulated transcription factor activity | IDA PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C... | NEW | 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. 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. Supporting Evidence: PMID:25554789 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 PMID:25554789 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 file:worm/nhr-80/nhr-80-deep-research-falcon.md 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. |
| GO:0016922 nuclear receptor binding | IPI PMID:22511885 Coordinate regulation of lipid metabolism by novel nuclear r... | NEW | 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. 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. Supporting Evidence: PMID:22511885 In addition, it was also able to interact directly with NHR-66 and NHR-80 file:worm/nhr-80/nhr-80-deep-research-falcon.md NHR-80 serves as a **binding partner/cofactor of NHR-49**, and the pair regulates subsets of lipid-metabolism genesβespecially desaturases. |
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