Gene Ontology annotation through association of InterPro records with GO terms

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.

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

UniProt subcellular location maps NHR-80 to nucleus, consistent with experimental data from NHR-80 GFP localization studies.

PMID:16839188

Genetic regulation of unsaturated fatty acid composition in C. elegans.

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.

"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"
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).

"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"
fat-7 expression is almost completely eliminated in nhr-80 mutants; fat-5 reduced 66%; fat-6 reduced 22%.

"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"
NHR-80 is required for compensatory upregulation of fat-7 when fat-6 is lost. fat-6;nhr-80 double mutants are synthetically lethal.

"The fat-6 mutants, when grown on nhr-80(RNAi) from eggs, become thin, slow growing, and reproductively inviable after 4 d of growth"
nhr-80 mutants have a slightly shorter lifespan (~10%) than wild type but much longer than nhr-49 mutants.

"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"

PMID:21423649

Fatty acid desaturation links germ cell loss to longevity through NHR-80/HNF4 in C. elegans.

NHR-80 is specifically required for germline-mediated longevity but not for daf-2, dietary restriction, or mitochondrial longevity pathways.

"nhr-80/HNF4 is induced in animals lacking a germ line and is specifically required for their extended longevity"
NHR-80::GFP localizes constitutively to nuclei in intestine and neurons; intensity increases 1.6-fold in germline-less animals.

"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"
nhr-80 mRNA is induced 5.6-fold in glp-1(e2141ts) mutant animals.

"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)"
NHR-80 overexpression extends glp-1 lifespan by 80% but does not extend wild-type lifespan.

"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)"
NHR-80 functions independently of DAF-16 but requires DAF-12 for longevity.

"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"
fat-6 is a key NHR-80 target in the germline-less longevity context.

"fat-6 Is Induced in glp-1(e2141ts) Mutant Animals in a NHR-80 Dependent Manner"

PMID:22511885

Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships.

NHR-49 and NHR-80 physically interact directly, as shown by yeast two-hybrid and in vitro GST pull-down assays.

"it was also able to interact directly with NHR-66 and NHR-80"
NHR-49/NHR-80 partnership activates desaturase genes; NHR-49/NHR-66 partnership represses sphingolipid genes.

"NHR-49 (blue) binds to NHR-80 (green) to activate the fatty acid desaturase genes"
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.

"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"
nhr-80;nhr-13 double mutants have lifespan approaching nhr-49 mutants, with C18:0/C18:1n9 ratio correlated to lifespan.

"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"
nhr-80 mutants show abnormal mitochondrial morphology.

"nhr-49, nhr-66, and nhr-80 animals have abnormal mitochondrial phenotypes"

PMID:25554789

Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans.

OEA directly binds to NHR-80 protein and activates transcription of NHR-49/NHR-80 target genes.

"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"
NHR-80 is required for LIPL-4 and LBP-8 mediated longevity extension.

"The loss-of-function mutation nhr-80(tm1011) abrogated longevity extension without affecting the lifespan of WT worms"
acs-2 transcription is increased more than 15-fold in lipl-4 Tg animals in an nhr-49 and nhr-80 dependent manner.

"acs-2 transcription was increased more than 15-fold in lipl-4 Tg animals; this effect was dependent on nhr-49 and nhr-80"
OEA analogue treatment increases transcription of lbp-8 (4-fold) and acs-2 (7-fold), abrogated in nhr-80(tm1011) mutant.

"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"

PMID:27001890

Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals.

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.

"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"
MML-1/MXL-2 Mondo complexes are required for germline-mediated longevity and regulate HLH-30/TFEB nuclear localization via TOR inhibition.

"mml-1 and mxl-2 deletions abolished lifespan extension in glp-1 mutants and in animals whose germline precursors were removed by laser microsurgery"

PMID:35021096

NHR-80 senses the mitochondrial UPR to rewire citrate metabolism for lipid accumulation in Caenorhabditis elegans.

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.

PMID:35140229

Histone H3K4me3 modification is a transgenerational epigenetic signal for lipid metabolism in Caenorhabditis elegans.

NHR-80 is required for transgenerational lipid accumulation in response to high-fat diet in C. elegans.

file:worm/nhr-80/nhr-80-deep-research-falcon.md

Falcon deep research report on C. elegans nhr-80 (UniProt Q8ITW8)

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.

"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."
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.

"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."
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.

"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."
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.

"NHR-80 then binds/transactivates lipogenic genes including **dgat-2** and desaturases. This connects mitochondrial surveillance to lipid storage/remodeling programs."