nhr-49

UniProt ID: O45666
Organism: Caenorhabditis elegans
Review Status: IN PROGRESS
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Gene Description

NHR-49 is an orphan nuclear hormone receptor of the HNF4 family that serves as a central transcriptional regulator of lipid metabolism in C. elegans, functionally analogous to mammalian PPARalpha. NHR-49 controls two major metabolic branches: (1) fatty acid beta-oxidation, by promoting expression of acs-2, ech-1, cpt-5, and other mitochondrial beta-oxidation genes, and (2) fatty acid desaturation, by activating delta-9 desaturases fat-5 and fat-7 (with modest effects on fat-6). NHR-49 operates through distinct heterodimeric partnerships: NHR-49/NHR-80 regulates desaturation genes, NHR-49/NHR-66 represses sphingolipid and lipid remodeling genes, and NHR-49/NHR-13 also contributes to desaturase regulation. NHR-49 also interacts with the Mediator subunit MDT-15 as a transcriptional coactivator. Loss of nhr-49 causes dramatically shortened lifespan (~41% reduction), increased fat storage, and altered fatty acid composition with elevated stearic-to-oleic acid ratio. NHR-49 is required for LIPL-4/LBP-8-mediated longevity signaling (acting as a cofactor with NHR-80, which is the direct OEA receptor), for germline-loss-mediated longevity (where it is transcriptionally upregulated by DAF-16 and TCER-1), and for hypoxia adaptation in parallel with HIF-1. NHR-49 also participates in transgenerational epigenetic inheritance of lipid accumulation from high-fat diet, functioning as an executor but not a transmitter of heritable memory. NHR-49 is expressed broadly in somatic tissues including intestine, neurons, hypodermis, and muscle, localizing to both nucleus and cytoplasm. It is an orphan receptor with no confirmed endogenous ligand; NHR-49 does not bind oleoylethanolamide (OEA), unlike its partner NHR-80.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005634 nucleus
IBA
GO_REF:0000033 		ACCEPT
Summary: NHR-49 is a nuclear hormone receptor with a predicted nuclear localization based on its DNA-binding domain (PROSITE-ProRule:PRU00407). Multiple experimental studies confirm nuclear localization: NHR-49::GFP is visible in nuclei of neurons, muscle, hypodermis, and intestinal cells (PMID:25474470), and nuclear localization is increased upon germline removal. The IBA annotation from phylogenetic inference is fully consistent with these experimental data.
Reason: Nuclear localization is a core feature of NHR-49 as a nuclear hormone receptor transcription factor. IDA evidence (PMID:25474470) directly confirms this IBA annotation. NHR-49::GFP localizes to nuclei in multiple somatic tissues. Falcon deep research notes NHR-49 is broadly expressed in multiple tissues including intestine and neurons.
Supporting Evidence:
PMID:25474470
NHR-49::GFP is visible in the cytoplasm and nuclei of neurons (E), muscle (F), hypodermis (G) and intestinal cells (H).
file:worm/nhr-49/nhr-49-deep-research-falcon.md
Broadly expressed in multiple tissues, including **intestine** and **neurons**
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IBA
GO_REF:0000033 		ACCEPT
Summary: NHR-49 contains a conserved zinc-finger DNA-binding domain (HNF4-like, InterPro IPR049636) and functions as a transcription factor that activates target gene promoters including acs-2, fat-5, fat-7, and fmo-2 (PMID:15719061, PMID:22511885, PMID:35285794). The IBA annotation from phylogenetic inference is consistent with NHR-49 being a nuclear receptor that binds DNA in a sequence-specific manner, although direct cis-regulatory binding assays (e.g., ChIP) have not been published specifically for NHR-49.
Reason: NHR-49 has a well-characterized zinc-finger DNA-binding domain and controls transcription of specific target genes. The IBA annotation is phylogenetically sound for this HNF4 family member. It is reasonable that NHR-49 binds cis-regulatory regions of its target gene promoters to achieve the highly specific transcriptional effects documented across multiple studies. Falcon deep research describes NHR-49 as a sequence-specific transcription factor that both activates and represses metabolic gene programs.
Supporting Evidence:
PMID:15719061
Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid β-oxidation, three genes involved in fatty acid desaturation
PMID:22511885
We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors
file:worm/nhr-49/nhr-49-deep-research-falcon.md
NHR-49 acts as a **transcriptional regulator** that can both **activate** and **repress** metabolic gene programs
GO:0004879 nuclear receptor activity
IBA
GO_REF:0000033 		ACCEPT
Summary: NHR-49 is an established member of the nuclear hormone receptor family, containing both a zinc-finger DNA-binding domain and a ligand-binding domain (NR LBD, PROSITE PRU01189). It is classified as an orphan nuclear receptor, as no endogenous ligand has been confirmed (PMID:25554789 showed NHR-49 does not bind OEA). NHR-49 functions as a ligand-independent or orphan transcription factor that regulates lipid metabolism genes (PMID:15719061, PMID:22511885).
Reason: Nuclear receptor activity is a core molecular function of NHR-49. It has the characteristic NHR domain architecture (DBD + LBD) and functions as a transcriptional regulator through DNA binding and partner interactions. The IBA annotation accurately captures this fundamental function. Falcon deep research independently confirms NHR-49 as a sequence-specific nuclear receptor transcription factor functionally comparable to mammalian PPARalpha and HNF4alpha, and notes that despite a functionally important ligand-binding domain, no definitive endogenous ligand is established (orphan receptor).
Supporting Evidence:
PMID:15719061
deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span
PMID:25554789
no binding was detected between NHR-49 and OEA or OEA analogue
file:worm/nhr-49/nhr-49-deep-research-falcon.md
NHR-49 is a sequence-specific transcription factor of the nuclear receptor superfamily
file:worm/nhr-49/nhr-49-deep-research-falcon.md
a definitive endogenous ligand for NHR-49 is not established
GO:0006357 regulation of transcription by RNA polymerase II
IBA
GO_REF:0000033 		ACCEPT
Summary: NHR-49 is a transcription factor that regulates expression of numerous target genes involved in fatty acid beta-oxidation and desaturation (PMID:15719061), sphingolipid processing (PMID:22511885), hypoxia response (PMID:35285794), and autophagy genes. It works with the Mediator subunit MDT-15 as a transcriptional coactivator (PMID:16651656), placing it squarely in the Pol II transcription regulatory machinery.
Reason: Regulation of Pol II transcription is a core biological process for NHR-49. Multiple studies demonstrate its role in activating and repressing transcription of specific gene sets through partnerships with other NHRs and with the Mediator complex. The IBA annotation is well supported. Falcon deep research reinforces the central role of MDT-15 (Mediator subunit) as a critical co-regulator across NHR-49 transcriptional outputs in both metabolism and stress programs.
Supporting Evidence:
PMID:16651656
we report the identification of MDT-15, a subunit of the C. elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator
PMID:15719061
nhr-49 is extensively involved in the control of fatty acid metabolism, with a pronounced role in the promotion of mitochondrial β-oxidation and fatty acid desaturation
file:worm/nhr-49/nhr-49-deep-research-falcon.md
MDT-15 (Mediator subunit)** as a critical co-regulator for NHR-49-driven transcriptional outputs
GO:0030154 cell differentiation
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: There is no direct experimental evidence that NHR-49 plays a role in cell differentiation in C. elegans. The original Van Gilst 2005 study explicitly noted that nhr-49 deletion did not noticeably affect development or fertility (PMID:15719061). NHR-49 is primarily a metabolic regulator. The IBA annotation may reflect a conserved role in HNF4 family members in vertebrates (where HNF4alpha has roles in liver and intestinal differentiation), but this function has not been demonstrated for nhr-49 in C. elegans.
Reason: While HNF4 family members in vertebrates play roles in cell differentiation, NHR-49 in C. elegans is characterized as a metabolic regulator with no documented role in cell differentiation. Loss of nhr-49 does not affect development or fertility (PMID:15719061). This IBA annotation likely over-extrapolates from vertebrate HNF4 functions that are not conserved in the nematode lineage. Falcon deep research consistently characterizes NHR-49 as a metabolic and stress-resilience regulator with no documented role in cell differentiation, supporting this over-annotation call.
Supporting Evidence:
PMID:15719061
Although nhr-49 deletion did not noticeably affect development or fertility, nhr-49(nr2041) worms experienced rapid decline in function beginning around day 3 of adulthood
file:worm/nhr-49/nhr-49-deep-research-falcon.md
NHR-49 coordinates transcriptional programs that balance lipid catabolism
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IEA
GO_REF:0000002 		ACCEPT
Summary: This IEA annotation from InterPro domain mapping duplicates the IBA annotation for the same term. NHR-49 contains a HNF4-like DNA-binding domain (InterPro IPR049636) and a nuclear receptor zinc finger (IPR001628), consistent with sequence-specific DNA binding at Pol II cis-regulatory regions.
Reason: The InterPro-based IEA annotation is consistent with NHR-49 domain architecture and its demonstrated function as a transcription factor. It is broader than the IBA annotation for the same term, but both are acceptable annotations for the same GO term from different evidence sources.
Supporting Evidence:
PMID:15719061
Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid β-oxidation, three genes involved in fatty acid desaturation
GO:0003700 DNA-binding transcription factor activity
IEA
GO_REF:0000002 		ACCEPT
Summary: NHR-49 is a well-established DNA-binding transcription factor that regulates expression of multiple target genes. However, the more specific term GO:0004879 (nuclear receptor activity) is already annotated via IBA and better captures the molecular function. This broader IEA term is not wrong but is less informative than the more specific nuclear receptor activity annotation.
Reason: While GO:0004879 (nuclear receptor activity) is more specific and already annotated, this broader IEA annotation from InterPro is not incorrect. It is acceptable to retain both a broader IEA and a more specific IBA annotation for the same gene.
Supporting Evidence:
PMID:15719061
nhr-49 is extensively involved in the control of fatty acid metabolism, with a pronounced role in the promotion of mitochondrial β-oxidation and fatty acid desaturation
GO:0005634 nucleus
IEA
GO_REF:0000044 		ACCEPT
Summary: This IEA annotation from UniProt subcellular location mapping is consistent with NHR-49 nuclear localization confirmed by IDA evidence (PMID:25474470) and IBA. UniProt lists nuclear localization based on PROSITE-ProRule:PRU00407.
Reason: The IEA annotation is correct and supported by multiple lines of experimental evidence for nuclear localization. It duplicates the IBA and IDA annotations for the same term but from a different evidence source, which is acceptable.
Supporting Evidence:
PMID:25474470
NHR-49::GFP is visible in the cytoplasm and nuclei of neurons (E), muscle (F), hypodermis (G) and intestinal cells (H).
GO:0006355 regulation of DNA-templated transcription
IEA
GO_REF:0000002 		ACCEPT
Summary: This IEA annotation is a broader parent term of GO:0006357 (regulation of transcription by RNA polymerase II), which is annotated via IBA. NHR-49 clearly regulates DNA-templated transcription of numerous target genes (PMID:15719061, PMID:22511885, PMID:16651656).
Reason: The annotation is correct. While it is broader than the IBA annotation for Pol II-specific regulation, it is not incorrect to retain both. NHR-49 is fundamentally a transcriptional regulator.
Supporting Evidence:
PMID:15719061
Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes
GO:0008270 zinc ion binding
IEA
GO_REF:0000002 		ACCEPT
Summary: NHR-49 contains two NR C4-type zinc finger motifs (residues 11-31 and 47-71) within its DNA-binding domain, as annotated in UniProt based on PROSITE-ProRule:PRU00407. Zinc coordination is essential for the structural integrity of the nuclear receptor DNA-binding domain.
Reason: The zinc ion binding annotation is correct based on the well-characterized C4-type zinc finger motifs in the NHR-49 DNA-binding domain. This is a structural feature inherent to all nuclear hormone receptors.
Supporting Evidence:
PMID:15719061
nhr-49(nr2041), which harbors a deletion in the nhr-49 gene encompassing part of the DNA binding domain and more than half of the ligand binding domain
GO:0030522 intracellular receptor signaling pathway
IEA
GO_REF:0000108 		ACCEPT
Summary: NHR-49 is an intracellular (nuclear) receptor that transduces signals by regulating transcription. Although it is an orphan receptor with no confirmed endogenous ligand, NHR-49 functions as a cofactor with NHR-80 in the LIPL-4/LBP-8/OEA lysosome-to-nucleus signaling pathway (PMID:25554789) and responds to germline signals via DAF-16/TCER-1 upregulation (PMID:25474470). The annotation derived from logical inference based on the nuclear receptor activity annotation is reasonable.
Reason: NHR-49 participates in intracellular receptor signaling as a nuclear receptor transcription factor. Even though it is orphan (no direct ligand), it functions within signaling pathways that regulate its activity and target gene expression. The IEA annotation from logical inference is appropriate. Falcon deep research reaffirms NHR-49 as an orphan nuclear receptor whose ligand-binding domain is functionally important but for which no definitive endogenous ligand is established.
Supporting Evidence:
PMID:25554789
Nuclear hormone receptors nhr-49 and nhr-80, previously demonstrated to physically interact (10), were both required for lipl-4–and lbp-8–mediated longevity
PMID:25474470
NHR-49 is transcriptionally up-regulated by DAF-16 and TCER-1 in the soma upon germline removal
file:worm/nhr-49/nhr-49-deep-research-falcon.md
a definitive endogenous ligand for NHR-49 is not established
GO:0043565 sequence-specific DNA binding
IEA
GO_REF:0000002 		ACCEPT
Summary: NHR-49 contains a conserved HNF4-like DNA-binding domain with two C4-type zinc fingers. This IEA annotation is a parent of the more specific GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding) already annotated. It is correct but less specific.
Reason: The annotation is correct. NHR-49 binds DNA in a sequence-specific manner through its zinc finger DNA-binding domain. While more specific annotations exist, the IEA from InterPro is not incorrect.
Supporting Evidence:
PMID:15719061
nhr-49 is extensively involved in the control of fatty acid metabolism, with a pronounced role in the promotion of mitochondrial β-oxidation and fatty acid desaturation
GO:0005515 protein binding
IPI
PMID:14704431
A map of the interactome network of the metazoan C. elegans. 		MODIFY
Summary: PMID:14704431 (Li et al. 2004) reports a high-throughput yeast two-hybrid interactome mapping study for C. elegans. NHR-49 was identified as an interactor in this screen. However, the generic term protein binding is uninformative. From subsequent focused studies, NHR-49 has been shown to physically interact with specific partners including NHR-80, NHR-66, NHR-13, and MDT-15 (PMID:22511885, PMID:16651656). A more specific term such as DNA-binding transcription factor binding (GO:0140297) would be more appropriate.
Reason: Protein binding is too vague for NHR-49, whose protein interactions are well characterized. The high-throughput Y2H screen identified interactions that are better captured by more specific terms. NHR-49 interacts with other transcription factors (NHR-80, NHR-66, NHR-13) and the Mediator coactivator MDT-15. GO:0140297 (DNA-binding transcription factor binding) better describes these interactions.
Supporting Evidence:
PMID:22511885
We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors
PMID:16651656
we report the identification of MDT-15, a subunit of the C. elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator
GO:0005515 protein binding
IPI
PMID:16651656
A Mediator subunit, MDT-15, integrates regulation of fatty a... 		MODIFY
Summary: PMID:16651656 (Taubert et al. 2006) identified MDT-15, a Mediator subunit, as a physical interacting partner and transcriptional coactivator of NHR-49. The interaction was shown through yeast two-hybrid and functional studies. The generic protein binding term fails to capture this specific and functionally important interaction with the Mediator complex.
Reason: The interaction between NHR-49 and MDT-15 (Mediator subunit) represents a transcription factor-coactivator interaction. GO:0140297 (DNA-binding transcription factor binding) is more appropriate, as MDT-15 is itself a transcriptional coregulator.
Supporting Evidence:
PMID:16651656
we report the identification of MDT-15, a subunit of the C. elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator. Knockdown of mdt-15 by RNA interference (RNAi) prevented fasting-induced mRNA accumulation of NHR-49 targets in vivo
GO:0005515 protein binding
IPI
PMID:19123269
Empirically controlled mapping of the Caenorhabditis elegans... 		MODIFY
Summary: PMID:19123269 (Simonis et al. 2009) is a high-throughput yeast two-hybrid interactome mapping study that provides expanded coverage of C. elegans protein-protein interactions. Similar to PMID:14704431, the generic protein binding term is uninformative for NHR-49, whose specific interaction partners are well characterized.
Reason: As with the other protein binding annotations, a more specific term is warranted. NHR-49 interacts with other NHRs and the Mediator complex. GO:0140297 (DNA-binding transcription factor binding) better describes the interactions detected.
Supporting Evidence:
PMID:22511885
We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors
GO:0005515 protein binding
IPI
PMID:23791784
Extensive rewiring and complex evolutionary dynamics in a C.... 		MODIFY
Summary: PMID:23791784 (Reece-Hoyes et al. 2013) characterized transcription factor network rewiring in C. elegans through systematic Y2H and other interaction assays. The study found that even highly similar TFs often have different interaction partners. For NHR-49, this provides network context but the generic protein binding annotation is too vague.
Reason: The protein binding term is too generic for NHR-49. The interactions detected in this TF network study are primarily TF-TF interactions. GO:0140297 (DNA-binding transcription factor binding) is more specific and appropriate.
Supporting Evidence:
PMID:23791784
we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks
GO:0140297 DNA-binding transcription factor binding
IPI
PMID:22511885
Coordinate regulation of lipid metabolism by novel nuclear r... 		ACCEPT
Summary: PMID:22511885 (Pathare et al. 2012) demonstrated that NHR-49 physically interacts with multiple nuclear hormone receptors including NHR-80, NHR-66, NHR-13, NHR-22, NHR-79, NHR-105, and NHR-256, forming both homodimers and heterodimers. Direct physical interactions were confirmed for NHR-49/NHR-80 and NHR-49/NHR-66 by yeast two-hybrid and functional studies. This term accurately captures NHR-49 binding to other DNA-binding transcription factors.
Reason: This annotation accurately describes the well-characterized physical interactions between NHR-49 and other NHRs (NHR-80, NHR-66, NHR-13). The term is specific and informative, directly supported by the referenced study. Falcon deep research independently summarizes the context-dependent NHR partnerships (NHR-80 for desaturase genes, NHR-66 for sphingolipid/lipid remodeling genes).
Supporting Evidence:
PMID:22511885
We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors
PMID:22511885
Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation
file:worm/nhr-49/nhr-49-deep-research-falcon.md
NHR-49 was shown to regulate distinct gene subsets via **partnerships with other NHRs**
file:worm/nhr-49/nhr-49-deep-research-falcon.md
**NHR-80**: linked to regulation of **fatty-acid desaturase** genes.
GO:0045944 positive regulation of transcription by RNA polymerase II
IMP
PMID:24854345
PKG and NHR-49 signalling co-ordinately regulate short-term ... 		ACCEPT
Summary: PMID:24854345 (Huang et al. 2014) showed that NHR-49 acts in the intestine during short-term fasting to regulate lysosomal lipid accumulation, coordinating with PKG/EGL-4 signaling. NHR-49 activates expression of IPLA-2 and other hydrolases in response to fasting. The positive regulation of transcription annotation is consistent with NHR-49 activating target gene expression in this context.
Reason: NHR-49 positively regulates transcription of target genes including acs-2, fat-5, fat-7, fmo-2, and genes involved in fasting responses. The IMP evidence from the fasting study supports this annotation, though the annotation captures a general function rather than the specific fasting context.
Supporting Evidence:
PMID:24854345
NHR-49 acts in intestine to inhibit lipids accumulation via activation of IPLA-2
GO:0008340 determination of adult lifespan
IGI
PMID:24107417
TAF-4 is required for the life extension of isp-1, clk-1 and... 		ACCEPT
Summary: PMID:24107417 (Khan et al. 2013) identified NHR-49 among transcription factors whose RNAi knockdown affected development, stress response, or fecundity of isp-1 mitochondrial (Mit) mutants. The study examined lifespan in Mit mutants. NHR-49 is listed alongside HIF-1 and other TFs that affect Mit mutant lifespan. This is consistent with NHR-49 having a role in lifespan determination, particularly in the context of mitochondrial function.
Reason: NHR-49 has a well-established role in determination of adult lifespan. Loss of nhr-49 causes ~41% reduction in lifespan (PMID:15719061, PMID:16839188), and it is required for longevity mediated by germline loss (PMID:25474470) and LIPL-4 signaling (PMID:25554789). The IGI evidence from the Mit mutant context adds another dimension to this core function.
Supporting Evidence:
PMID:24107417
Seven of these transcription factors--AHA-1, CEH-18, HIF-1, JUN-1, NHR-27, NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein TAF-4--were also essential for isp-1 life extension.
PMID:15719061
nhr-49(nr2041) worms lived only 6–8 d as adults, significantly shorter than the 15 to 18-d life span of N2 wild-type (WT) animals
GO:0005634 nucleus
IDA
PMID:25474470
Germline signals deploy NHR-49 to modulate fatty-acid β-oxid... 		ACCEPT
Summary: PMID:25474470 (Ratnappan et al. 2014) directly demonstrated NHR-49::GFP localization to both nuclei and cytoplasm in adult somatic tissues, with highest expression in intestinal cells. Nuclear localization was especially prominent upon germline removal.
Reason: Direct experimental evidence using NHR-49::GFP fusion protein confirms nuclear localization in multiple tissues. This is a core annotation for a nuclear hormone receptor.
Supporting Evidence:
PMID:25474470
In adults, it was visible in all somatic tissues (Fig
GO:0005737 cytoplasm
IDA
PMID:25474470
Germline signals deploy NHR-49 to modulate fatty-acid β-oxid... 		ACCEPT
Summary: PMID:25474470 (Ratnappan et al. 2014) showed NHR-49::GFP localization to both nuclei and cytoplasm in adult somatic tissues. Cytoplasmic localization was evident alongside nuclear localization in neurons, muscle, hypodermis, and intestinal cells.
Reason: Direct experimental evidence confirms cytoplasmic localization of NHR-49. This likely reflects the dynamic shuttling of nuclear receptors between cytoplasm and nucleus. The dual localization is common for nuclear hormone receptors.
Supporting Evidence:
PMID:25474470
In adults, it was visible in all somatic tissues (Fig
GO:0005634 nucleus
HDA
PMID:21611156
Determining the sub-cellular localization of proteins within... 		ACCEPT
Summary: PMID:21611156 (Meissner et al. 2011) is a high-throughput localizome study determining sub-cellular localization of proteins within C. elegans body wall muscle using GFP tagging. NHR-49 was localized to the nucleus in this study. While this is body wall muscle-specific data, it is consistent with the broader expression and localization data from PMID:25474470.
Reason: The HDA evidence from the muscle localizome study confirms nuclear localization and is consistent with the IDA evidence from PMID:25474470 and the predicted nuclear localization from domain analysis.
Supporting Evidence:
PMID:21611156
we have analyzed the expression of about 227 GFP-tagged proteins that show localized expression in the body wall muscle of this nematode
GO:0008340 determination of adult lifespan
IMP
PMID:15719061
Nuclear hormone receptor NHR-49 controls fat consumption and... 		ACCEPT
Summary: PMID:15719061 (Van Gilst et al. 2005) is the seminal study characterizing NHR-49 function. It demonstrated that nhr-49(nr2041) deletion mutants have dramatically shortened lifespan (6-8 days vs. 15-18 days for wild type at 23C), representing approximately 41% reduction in adult lifespan. The authors showed a striking correlation between fatty acid desaturase activity (stearic/oleic acid ratio) and lifespan, suggesting the shortened lifespan results at least in part from impaired fat-7 expression.
Reason: Determination of adult lifespan is a core phenotype of nhr-49 loss of function. The ~41% reduction in lifespan is one of the most dramatic effects reported for nhr-49 mutants and has been replicated across multiple studies. Falcon deep research lists shortened lifespan among the core loss-of-function phenotypes of nhr-49.
Supporting Evidence:
PMID:15719061
nhr-49(nr2041) worms lived only 6–8 d as adults, significantly shorter than the 15 to 18-d life span of N2 wild-type (WT) animals
PMID:15719061
nhr-49 function is not required for development or fertility, but is clearly essential for normal longevity
file:worm/nhr-49/nhr-49-deep-research-falcon.md
Loss of **nhr-49** causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology and function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection
GO:0019217 regulation of fatty acid metabolic process
IMP
PMID:15719061
Nuclear hormone receptor NHR-49 controls fat consumption and... 		ACCEPT
Summary: PMID:15719061 (Van Gilst et al. 2005) comprehensively demonstrated that NHR-49 regulates expression of 13 fatty acid metabolism genes, including six in beta-oxidation (acs-2, ech-1, F09F3.9), three delta-9 desaturases (fat-5, fat-7, and to a lesser extent fat-6), and genes in fatty acid binding/transport and the glyoxylate pathway. Loss of nhr-49 results in increased fat storage and altered fatty acid composition with elevated stearic-to-oleic acid ratio.
Reason: Regulation of fatty acid metabolism is the most central function of NHR-49. The evidence from PMID:15719061 is comprehensive, showing effects on both beta-oxidation and desaturation pathways, with measurable changes in fat storage and fatty acid composition. Falcon deep research confirms the central role of NHR-49 in activating beta-oxidation targets (acs-2, cpt-5, ech-1) and desaturase genes (fat-5, fat-6, fat-7).
Supporting Evidence:
PMID:15719061
Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid β-oxidation, three genes involved in fatty acid desaturation
PMID:15719061
nhr-49(nr2041) animals stained more brightly with Nile Red than did WT worms
file:worm/nhr-49/nhr-49-deep-research-falcon.md
It activates gene modules involved in **fatty-acid β-oxidation** (including canonical targets such as **acs-2, cpt-5, ech-1**) and regulates **fatty-acid desaturation** genes (**fat-5, fat-6, fat-7**)
GO:0045944 positive regulation of transcription by RNA polymerase II
IMP
PMID:15719061
Nuclear hormone receptor NHR-49 controls fat consumption and... 		ACCEPT
Summary: PMID:15719061 (Van Gilst et al. 2005) showed that NHR-49 promotes transcription of target genes including acs-2, fat-5, fat-7, and ech-1. Expression of these genes was dramatically reduced (>30-fold for fat-5 and fat-7) in nhr-49 deletion mutants. NHR-49 also works with Mediator subunit MDT-15 for transcriptional activation (PMID:16651656).
Reason: Positive regulation of Pol II transcription is a core molecular function of NHR-49 as a transcription factor that activates expression of fatty acid metabolism genes. The evidence is strong and direct.
Supporting Evidence:
PMID:15719061
fat-5 (W06D12.3) and fat-7 (F10D2.9) expression was dramatically lowered in nhr-49(nr2041) worms (>30-fold) in all four larval stages
PMID:16651656
Knockdown of mdt-15 by RNA interference (RNAi) prevented fasting-induced mRNA accumulation of NHR-49 targets in vivo
GO:0008340 determination of adult lifespan
IMP
PMID:16839188
Genetic regulation of unsaturated fatty acid composition in ... 		ACCEPT
Summary: PMID:16839188 (Brock et al. 2006) characterized nhr-80 and delta-9 desaturase mutants, with nhr-49 as a comparison. The study confirmed that nhr-49 mutants have a 41% reduction in mean lifespan (8.2 days vs 13.9 days at 25C) and importantly showed that nhr-80 mutants, despite similar fatty acid composition changes, have only a modest ~10% lifespan reduction. This demonstrates that the short lifespan of nhr-49 is not solely due to desaturase deficiency but involves additional metabolic functions (e.g., beta-oxidation).
Reason: This provides independent replication of the nhr-49 lifespan phenotype and adds the important insight that the lifespan effect is not solely attributable to desaturase regulation. Determination of adult lifespan is a core function of nhr-49.
Supporting Evidence:
PMID:16839188
These data indicate a 10% decrease in mean lifespan between wild type and nhr-80 mutants, the difference between wild type and nhr-49 mutants is much greater with a 41% reduction in mean lifespan.
GO:0019216 regulation of lipid metabolic process
IMP
PMID:16839188
Genetic regulation of unsaturated fatty acid composition in ... 		ACCEPT
Summary: PMID:16839188 (Brock et al. 2006) confirmed that nhr-49 mutants have altered fatty acid composition similar to nhr-80 mutants (elevated 18:0/18:1 ratio), but additionally showed increased fat storage not seen in nhr-80 mutants. NHR-49 regulates both desaturation (via fat-5, fat-7) and beta-oxidation pathways, having broader lipid regulatory functions than NHR-80 alone.
Reason: Regulation of lipid metabolism is a core function of NHR-49. While GO:0019217 (regulation of fatty acid metabolic process) from PMID:15719061 is more specific, this broader term also captures NHR-49 roles in sphingolipid processing and lipid remodeling (PMID:22511885) that go beyond fatty acid metabolism. Falcon deep research describes NHR-49 as coordinating transcriptional programs that balance lipid catabolism, fatty-acid desaturation, and lipid remodeling, including NHR-66-dependent sphingolipid/lipid remodeling programs.
Supporting Evidence:
PMID:16839188
The nhr-49 mutants have increased levels of the saturated fatty acid 18:0, higher fat accumulation, and a shorter lifespan than wild-type animals
PMID:22511885
We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors
file:worm/nhr-49/nhr-49-deep-research-falcon.md
**NHR-66**: linked to regulation of **sphingolipid/lipid remodeling** genes.
GO:0071456 cellular response to hypoxia
IMP
PMID:35285794
Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 ... 		NEW
Summary: PMID:35285794 (Doering et al. 2022) demonstrated that NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation. Under 0.5% oxygen, NHR-49 activates expression of acs-2, fmo-2, and autophagy-related genes. Loss of nhr-49 reduces embryonic hypoxia survival from 86% to 25%. Combined loss of nhr-49 and hif-1 is nearly lethal under hypoxia (<2% survival). NHR-49 acts in multiple somatic tissues including intestine, head neurons, and hypodermal seam cells.
Reason: This annotation captures the well-documented role of NHR-49 in hypoxia adaptation, which is a distinct biological function from its lipid metabolism role. The evidence from Doering et al. 2022 is strong with clear survival phenotypes and target gene identification. Falcon deep research highlights this as an essential hypoxia survival pathway acting in parallel to HIF-1, with NHR-49 required for hypoxia-induced autophagosome (LGG-1::GFP) formation in seam cells.
Supporting Evidence:
PMID:35285794
nhr-49 is not only required to induce fmo-2, but controls a broad transcriptional response to hypoxia
file:worm/nhr-49/nhr-49-deep-research-falcon.md
an **essential hypoxia survival pathway** controlled by NHR-49 that operates **in parallel to HIF-1**
file:worm/nhr-49/nhr-49-deep-research-falcon.md
NHR-49 being required for hypoxia-induced autophagosome formation (LGG-1::GFP foci) in seam cells

Core Functions

NHR-49 acts as a nuclear receptor transcription factor to regulate fatty acid metabolism genes through heterodimerization with partner NHRs. The NHR-49/NHR-80 heterodimer activates delta-9 desaturase genes (fat-5, fat-7), while NHR-49/NHR-66 represses sphingolipid and lipid remodeling genes. NHR-49 independently promotes beta-oxidation gene expression (acs-2, ech-1, cpt-5). The Mediator subunit MDT-15 serves as a transcriptional coactivator for NHR-49 target genes.

Molecular Function:
nuclear receptor activity
Directly Involved In:
regulation of fatty acid metabolic process
Cellular Locations:
nucleus
Supporting Evidence:
  • PMID:15719061
    Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid beta-oxidation, three genes involved in fatty acid desaturation
  • PMID:22511885
    We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors
  • PMID:16651656
    elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator

NHR-49 acts as a nuclear receptor cofactor required for longevity mediated by germline loss (glp-1) and LIPL-4/LBP-8 lysosomal lipid signaling. Upon germline removal, NHR-49 is transcriptionally upregulated by DAF-16/FOXO and TCER-1/TCERG1 and promotes beta-oxidation gene expression. In the LIPL-4/LBP-8/OEA pathway, NHR-49 acts together with NHR-80 (the direct OEA receptor) as a downstream effector. NHR-49 does not bind OEA directly. Loss of nhr-49 causes approximately 41% lifespan reduction and completely suppresses germline-loss longevity but is not required for daf-2/IIS longevity.

Molecular Function:
nuclear receptor activity
Directly Involved In:
determination of adult lifespan
Cellular Locations:
nucleus
Supporting Evidence:
  • PMID:25474470
    We found that two independent RNAi clones targeting nhr-49 completely abrogated the longevity of glp-1 mutants (Fig
  • PMID:25554789
    Nuclear hormone receptors nhr-49 and nhr-80, previously demonstrated to physically interact (10), were both required for lipl-4–and lbp-8–mediated longevity
  • PMID:15719061
    At 23 °C, nhr-49(nr2041) worms lived only 6–8 d as adults, significantly shorter than the 15 to 18-d life span of N2 wild-type (WT) animals (Figure 1A)

NHR-49 acts as a nuclear receptor transcription factor promoting hypoxia adaptation in parallel with HIF-1. Under 0.5% oxygen, NHR-49 activates expression of acs-2, fmo-2, and autophagy-related genes. NHR-49 acts in multiple somatic tissues including intestine, head neurons, and hypodermal seam cells. Loss of nhr-49 reduces embryonic hypoxia survival from 86% to 25%, and combined loss with hif-1 is nearly lethal under hypoxia.

Molecular Function:
nuclear receptor activity
Directly Involved In:
cellular response to hypoxia
Cellular Locations:
nucleus
Supporting Evidence:
  • PMID:35285794
    Here, we show that nhr-49 is not only required to induce fmo-2, but controls a broad transcriptional response to hypoxia, including the induction of autophagy, a process required within the nhr-49 pathway for survival in hypoxia

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000108
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
PMID:14704431
A map of the interactome network of the metazoan C. elegans.
  • High-throughput yeast two-hybrid screen identifying NHR-49 protein interactions in C. elegans.
    "more than 4000 interactions were identified from high-throughput, yeast two-hybrid (HT=Y2H) screens"
PMID:15719061
Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.
  • NHR-49 regulates fatty acid beta-oxidation genes (acs-2, ech-1) and desaturation genes (fat-5, fat-7), controlling fat consumption and fatty acid composition.
    "Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid β-oxidation, three genes involved in fatty acid desaturation"
  • nhr-49(nr2041) deletion causes approximately 41% lifespan reduction, increased fat storage, and elevated stearic-to-oleic acid ratio.
    "nhr-49(nr2041) worms lived only 6–8 d as adults, significantly shorter than the 15 to 18-d life span of N2 wild-type (WT) animals"
  • fat-7 RNAi reproduces the shortened lifespan phenotype of nhr-49 mutants, suggesting the lifespan defect results at least in part from impaired desaturase expression.
    "the effect of fat-7 RNAi on life span was even more potent than nhr-49 deletion, reducing adult life span to 3–5 d"
PMID:16651656
A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans.
  • MDT-15 identified as NHR-49 physical interacting partner and transcriptional coactivator for fatty acid metabolism gene regulation.
    "we report the identification of MDT-15, a subunit of the C. elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator"
  • MDT-15 also regulates fat-6 independently of NHR-49, indicating additional regulatory factors recruit MDT-15.
    "mdt-15 RNAi affected additional FA-metabolism genes (including the third FA-Δ9-desaturase, fat-6) that are regulated independently of NHR-49"
PMID:16839188
Genetic regulation of unsaturated fatty acid composition in C. elegans.
  • NHR-80 identified as a novel regulator of delta-9 desaturase expression with phenotypes similar to but distinct from nhr-49 mutants.
    "We found an RNAi clone, nhr-80, that caused C. elegans to accumulate increased levels of 18:0"
  • nhr-49 mutants have 41% lifespan reduction compared to only 10% for nhr-80 mutants despite similar fatty acid composition changes.
    "These data indicate a 10% decrease in mean lifespan between wild type and nhr-80 mutants, the difference between wild type and nhr-49 mutants is much greater with a 41% reduction in mean lifespan"
  • NHR-80 is required for compensatory upregulation of fat-7 in fat-6 mutants; fat-6;nhr-80 double mutants are synthetically lethal.
    "NHR-80 is required for increasing fat-7 expression in situations where higher fat-7 levels are necessary"
PMID:19123269
Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.
  • Expanded C. elegans interactome map from systematic Y2H screening including NHR-49 interactions.
    "we present an expanded C. elegans protein-protein interaction network"
PMID:21611156
Determining the sub-cellular localization of proteins within Caenorhabditis elegans body wall muscle.
  • High-throughput GFP-tagging localizome study showing NHR-49 nuclear localization in body wall muscle cells.
    "we have analyzed the expression of about 227 GFP-tagged proteins that show localized expression in the body wall muscle of this nematode"
PMID:22511885
Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships.
  • NHR-49 forms heterodimers with NHR-80 (desaturation pathway), NHR-66 (sphingolipid pathway), and NHR-13 (desaturation pathway).
    "We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors"
  • NHR-49 also homodimerizes and may interact with NHR-22, NHR-79, NHR-105, and NHR-256.
    "Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation"
  • nhr-49 mutants have altered mitochondrial morphology, and sphingolipid and lipid remodeling genes are newly identified NHR-49 targets.
    "nhr-49 animals had significantly altered mitochondrial morphology"
PMID:23791784
Extensive rewiring and complex evolutionary dynamics in a C. elegans multiparameter transcription factor network.
  • Systematic characterization of TF network rewiring showing NHR-49 interactions across multiple molecular networks in C. elegans.
    "we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks"
PMID:24107417
TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants.
  • NHR-49 identified among transcription factors with roles in development, stress response, and fecundity of isp-1 Mit mutants.
    "Seven of these transcription factors--AHA-1, CEH-18, HIF-1, JUN-1, NHR-27, NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein TAF-4--were also essential for isp-1 life extension."
PMID:24854345
PKG and NHR-49 signalling co-ordinately regulate short-term fasting-induced lysosomal lipid accumulation in C. elegans.
  • NHR-49 acts in intestine during short-term fasting to regulate lysosomal lipid accumulation via activation of IPLA-2 and lysosomal hydrolases.
    "NHR-49 acts in intestine to inhibit lipids accumulation via activation of IPLA-2"
  • EGL-4/PKG acts in sensory neurons while NHR-49 acts in intestine, coordinating the fasting-induced lysosomal response.
    "EGL-4 acts in sensory neurons to enhance lysosomal lipid accumulation through inhibiting the DAF-3/SMAD pathway, whereas NHR-49 acts in intestine"
PMID:25474470
Germline signals deploy NHR-49 to modulate fatty-acid β-oxidation and desaturation in somatic tissues of C. elegans.
  • NHR-49 is essential for germline-loss-mediated longevity in glp-1 mutants but dispensable for daf-2/IIS longevity.
    "nhr-49 has variable degrees of relevance for different physiological alterations that influence aging. It is critical for the longevity mediated by reproductive signals but is not central to the lifespan changes resulting from reduced IIS"
  • NHR-49 is transcriptionally upregulated by DAF-16 and TCER-1 in soma upon germline removal.
    "NHR-49 is transcriptionally up-regulated by DAF-16 and TCER-1 in the soma upon germline removal"
  • NHR-49::GFP localizes to nuclei and cytoplasm in all somatic tissues, with highest expression in intestinal cells.
    "In adults, it was visible in all somatic tissues (Fig"
  • NHR-49 controls expression of 7 mitochondrial beta-oxidation genes in germline-less animals and overexpression modestly extends fertile animal lifespan by approximately 15%.
    "NHR-49 causes the increased expression of multiple genes involved in fatty-acid β-oxidation and desaturation"
PMID:25554789
Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans.
  • NHR-49 and NHR-80 are both required for LIPL-4 and LBP-8 mediated longevity signaling.
    "Nuclear hormone receptors nhr-49 and nhr-80, previously demonstrated to physically interact (10), were both required for lipl-4–and lbp-8–mediated longevity"
  • NHR-49 does NOT bind OEA directly; NHR-80 is the direct nuclear receptor for OEA with Kd of approximately 7.8 uM.
    "no binding was detected between NHR-49 and OEA or OEA analogue"
  • acs-2 transcription increased more than 15-fold in lipl-4 Tg animals, dependent on both nhr-49 and nhr-80.
    "acs-2 transcription was increased more than 15-fold in lipl-4 Tg animals; this effect was dependent on nhr-49 and nhr-80"
PMID:35140229
Histone H3K4me3 modification is a transgenerational epigenetic signal for lipid metabolism in Caenorhabditis elegans.
  • NHR-49 is required for transgenerational inheritance of lipid accumulation from high-fat diet, functioning as an executor but not a transmitter of heritable lipid memory.
    "nhr-49 and nhr-80 functioned solely as executors"
  • nhr-49 mutation abrogates F1 and F2 lipid accumulation from parental HFD but does not affect P0 response to HFD.
    "lipid accumulation was abrogated in F1 or F2 descendants of these mutants"
  • NHR-49, NHR-80, SBP-1, and DAF-16 function in parallel pathways for transgenerational epigenetic inheritance of lipid accumulation.
    "daf-16, sbp-1, nhr-49 and nhr-80 function in parallel pathway during the stress of lipid accumulation in F1 generation"
PMID:35285794
Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation in Caenorhabditis elegans.
  • NHR-49 promotes hypoxia adaptation in parallel with HIF-1, activating acs-2, autophagy genes, and fmo-2 during hypoxia.
    "nhr-49 is not only required to induce fmo-2, but controls a broad transcriptional response to hypoxia"
  • nhr-49 loss reduces hypoxia survival from 86% to 25% for embryos developing to L4 stage.
    "only 25% of nhr-49 and hif-1 null mutant animals reached at least the L4 stage by that time"
  • NHR-49 is expressed in head, intestine, and hypodermal seam cells.
    "Expression is seen in the head, intestine, and hypodermal seam cells"
file:worm/nhr-49/nhr-49-deep-research-falcon.md
Falcon deep research report on nhr-49 (C. elegans)
  • NHR-49 is a sequence-specific transcription factor of the nuclear receptor superfamily, functionally comparable to mammalian lipid-sensing nuclear receptors (PPARalpha by functional analogy, HNF4alpha by structural similarity), and is among the best-characterized C. elegans NHRs.
    "**NHR-49 is a sequence-specific transcription factor of the nuclear receptor superfamily**. It is widely described as functionally comparable to mammalian lipid-sensing nuclear receptors, especially **PPARα** (functional analogy) and **HNF4α** (structural similarity), and is among the best-characterized *C. elegans* NHRs"
  • The central mechanistic theme is that NHR-49 coordinates transcriptional programs balancing lipid catabolism (beta-oxidation), fatty-acid desaturation, lipid remodeling, and stress-protective responses.
    "the central mechanistic theme is that **NHR-49 coordinates transcriptional programs that balance lipid catabolism (β-oxidation), fatty-acid desaturation, lipid remodeling, and stress-protective responses**"
  • NHR-49 acts as a transcriptional regulator that can both activate and repress metabolic gene programs, activating fatty-acid beta-oxidation targets (acs-2, cpt-5, ech-1) and regulating desaturases (fat-5, fat-6, fat-7).
    "**Primary function**: NHR-49 acts as a **transcriptional regulator** that can both **activate** and **repress** metabolic gene programs. - It activates gene modules involved in **fatty-acid β-oxidation** (including canonical targets such as **acs-2, cpt-5, ech-1**) and regulates **fatty-acid desaturation** genes (**fat-5, fat-6, fat-7**)"
  • NHR-49 regulates distinct gene subsets via context-dependent partnerships with other NHRs: NHR-80 for fatty-acid desaturase genes and NHR-66 for sphingolipid/lipid remodeling genes.
    "NHR-49 was shown to regulate distinct gene subsets via **partnerships with other NHRs**, notably: - **NHR-80**: linked to regulation of **fatty-acid desaturase** genes. - **NHR-66**: linked to regulation of **sphingolipid/lipid remodeling** genes."
  • MDT-15 (a Mediator subunit) is a critical co-regulator for NHR-49-driven transcriptional outputs in metabolism and stress programs.
    "Multiple studies converge on **MDT-15 (Mediator subunit)** as a critical co-regulator for NHR-49-driven transcriptional outputs in metabolism and stress programs"
  • NHR-49 is an orphan nuclear receptor: its ligand-binding domain is functionally important and likely ligand-responsive, but no definitive endogenous ligand has been established, so any ligand should be phrased as putative.
    "Evidence strongly supports that **the LBD is functionally important** and likely ligand-responsive, but **a definitive endogenous ligand for NHR-49 is not established**."
  • NHR-49 controls an essential hypoxia survival pathway that operates in parallel to HIF-1, being required for hypoxia-induced autophagosome (LGG-1::GFP) formation in seam cells.
    "A major mechanistic expansion beyond “lipid metabolism” is an **essential hypoxia survival pathway** controlled by NHR-49 that operates **in parallel to HIF-1**, with NHR-49 being required for hypoxia-induced autophagosome formation (LGG-1::GFP foci) in seam cells"
  • NHR-49/MDT-15 couples lipid metabolic remodeling to HSF-1-dependent heat shock response and proteostasis; intestinal NHR-49 activation improves proteostasis outcomes (Sala et al. 2024, Genes & Development).
    "A 2024 Genes & Development study places NHR-49/MDT-15 as a signaling module that links lipid metabolic remodeling to **HSF-1-dependent heat shock response** and proteostasis"
  • A cell-autonomous neuronal role for NHR-49 in oxygen-sensing URX/AQR/PQR neurons is required for pathogen (PA14) lawn avoidance and normal neuronal calcium kinetics (Kwon et al. 2024, Cells).
    "A 2024 Cells paper identifies a **cell-autonomous neuronal role**: loss of nhr-49 causes impaired pathogen lawn avoidance (PA14) associated with **prolonged URX calcium transients after O2 upshift**, and neuronal rescue in URX/AQR/PQR improves both behavior and calcium kinetics"
  • Loss of nhr-49 causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology/function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection.
    "Loss of **nhr-49** causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology and function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection"
  • NHR-49 is required for induction of phase II detoxification programs in oxidative stress contexts and works with MDT-15.
    "NHR-49 is required for induction of detoxification programs (phase II enzymes) in oxidative stress contexts and works with MDT-15"

Deep Research

Falcon

(nhr-49-deep-research-falcon.md)
Research Report: Functional Annotation of *Caenorhabditis elegans* **nhr-49** (UniProt **O45666**) Falcon Edison Scientific Literature 31 citations 2 artifacts 2026-05-30T17:56:09.571471
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000015 The requested figures showing hypoxia survival and LGG-1::GFP autophagy foci data are provided. Survival Data: - Figure 2A (cropped (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

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Research Report: Functional Annotation of Caenorhabditis elegans nhr-49 (UniProt O45666)

0) Target verification (mandatory disambiguation)

The target described in UniProt (O45666) is NHR-49, encoded by nhr-49 (ORF K10C3.6) in Caenorhabditis elegans, and belongs to the nuclear hormone receptor (NHR) family with canonical DNA-binding and ligand-binding domains typical of HNF4/NR2-related receptors. The literature extracted here consistently refers to the C. elegans nuclear hormone receptor NHR-49 with HNF4/PPARα-like roles in lipid metabolism and stress physiology, matching the UniProt-provided identity and domains (Frontiers review 2023-08-14; https://doi.org/10.3389/fphys.2023.1241591) (doering2023nuclearhormonereceptor pages 1-2).

1) Key concepts and definitions (current understanding)

1.1 What NHR-49 is

NHR-49 is a sequence-specific transcription factor of the nuclear receptor superfamily. It is widely described as functionally comparable to mammalian lipid-sensing nuclear receptors, especially PPARα (functional analogy) and HNF4α (structural similarity), and is among the best-characterized C. elegans NHRs (review published 2023-08-14; https://doi.org/10.3389/fphys.2023.1241591) (doering2023nuclearhormonereceptor pages 1-2).

1.2 Core molecular role

Across primary and review sources, the central mechanistic theme is that NHR-49 coordinates transcriptional programs that balance lipid catabolism (β-oxidation), fatty-acid desaturation, lipid remodeling, and stress-protective responses (doering2023nuclearhormonereceptor pages 1-2, pathare2012coordinateregulationof pages 2-3).

1.3 Nuclear receptor partnerships and co-regulators

A key concept for NHR-49 annotation is context-dependent partnering. In a major genetics study (PLOS Genetics, 2012-04; https://doi.org/10.1371/journal.pgen.1002645), NHR-49 was shown to regulate distinct gene subsets via partnerships with other NHRs, notably:
- NHR-80: linked to regulation of fatty-acid desaturase genes.
- NHR-66: linked to regulation of sphingolipid/lipid remodeling genes.
The same study used NHR-49’s ligand-binding domain (LBD) as bait in yeast two-hybrid screens and reported recovery of multiple candidate interacting factors (pathare2012coordinateregulationof pages 2-3, pathare2012coordinateregulationof pages 14-15).

2) Molecular function, localization, and pathway placement

2.1 Molecular function (what it “does”)

Primary function: NHR-49 acts as a transcriptional regulator that can both activate and repress metabolic gene programs.
- It activates gene modules involved in fatty-acid β-oxidation (including canonical targets such as acs-2, cpt-5, ech-1) and regulates fatty-acid desaturation genes (fat-5, fat-6, fat-7) (pathare2012coordinateregulationof pages 2-3).
- It is also implicated in stress-protective transcription, including oxidative-stress detoxification programs and regulation of detox genes (e.g., gst-4 in stress contexts) (G3, 2018-12; https://doi.org/10.1534/g3.118.200727) (hu2018thecaenorhabditiselegans pages 1-5).

Coactivator dependence: Multiple studies converge on MDT-15 (Mediator subunit) as a critical co-regulator for NHR-49-driven transcriptional outputs in metabolism and stress programs (hu2018thecaenorhabditiselegans pages 1-5, sala2024nuclearreceptorsignaling pages 1-2).

2.2 Ligand-binding: evidence and current limitations

Evidence strongly supports that the LBD is functionally important and likely ligand-responsive, but a definitive endogenous ligand for NHR-49 is not established.
- Gain-of-function missense mutations in the LBD (PLoS ONE, 2016-09-12; https://doi.org/10.1371/journal.pone.0162708) broadly increase NHR-49-regulated gene expression; structural modeling in that paper supports potential interaction with small molecules (lee2016gainoffunctionallelesin pages 1-2).
- A 2024 PLOS Biology paper proposes that palmitic acid functions as a ligand activating “NHR-49/80” to trigger early development under starvation, but the excerpted evidence notes that direct binding was not conclusively verified (kwon2024regulatoroflipid pages 9-11).
Taken together: ligand regulation is plausible and an active area, but functional annotation should phrase ligands as “putative/proposed” unless binding is directly shown.

2.3 Tissue and cellular localization (where it acts)

The most consistent localization evidence is functional, tissue-specific rescue and transgenic expression.
- Neurons (cell-autonomous behavior control): A 2024 Cells paper (2024-06; https://doi.org/10.3390/cells13110978) shows NHR-49 function in specific oxygen-sensing body cavity neurons (URX, AQR, PQR) is sufficient to restore pathogen avoidance behaviors and normalize neuronal calcium kinetics (kwon2024regulatoroflipid pages 1-2, kwon2024regulatoroflipid pages 9-11).
- Intestine (metabolic and proteostasis programs): A 2024 Genes & Development study (2024-05; https://doi.org/10.1101/gad.351829.124) uses intestinal promoters (e.g., gly-19p::nhr-49::gfp) and shows that intestinal NHR-49 activation improves proteostasis outcomes (sala2024nuclearreceptorsignaling pages 7-8).
- Multi-tissue rescue in hypoxia adaptation: eLife 2022 includes tissue-specific constructs (intestine, hypodermis, neurons, muscle) in defining an essential NHR-49 hypoxia pathway (2022-03; https://doi.org/10.7554/elife.67911) (doering2022nuclearhormonereceptor pages 8-11).

3) Key biological processes and pathways regulated by NHR-49

3.1 Lipid catabolism and fatty-acid β-oxidation (mitochondrial/peroxisomal)

In the canonical model, NHR-49 drives expression of fatty-acid utilization genes, including acs-2, cpt-5, ech-1, linking it to β-oxidation and lipid consumption pathways (pathare2012coordinateregulationof pages 2-3).

3.2 Fatty-acid desaturation and membrane lipid composition

NHR-49 regulates Δ9-desaturase genes fat-5/fat-6/fat-7, connecting it to MUFA production and lipid composition (pathare2012coordinateregulationof pages 2-3). A 2024 neuronal study further connects altered lipid composition in nhr-49 mutants to altered neuronal activity (kwon2024regulatoroflipid pages 9-11).

3.3 Lipid remodeling and sphingolipid programs via nuclear receptor partnerships

Pathare et al. (2012-04; https://doi.org/10.1371/journal.pgen.1002645) is central evidence that NHR-49’s downstream outputs partition into distinct modules depending on partner receptor context (notably NHR-66 and NHR-80), including sphingolipid/lipid remodeling genes (pathare2012coordinateregulationof pages 1-2, pathare2012coordinateregulationof pages 2-3).

3.4 Oxidative-stress and xenobiotic detoxification

NHR-49 is required for induction of detoxification programs (phase II enzymes) in oxidative stress contexts and works with MDT-15; it can also influence SKN-1 isoform expression in this context (G3, 2018-12; https://doi.org/10.1534/g3.118.200727) (hu2018thecaenorhabditiselegans pages 1-5).

3.5 Hypoxia adaptation via autophagy gene regulation (HIF-independent arm)

A major mechanistic expansion beyond “lipid metabolism” is an essential hypoxia survival pathway controlled by NHR-49 that operates in parallel to HIF-1, with NHR-49 being required for hypoxia-induced autophagosome formation (LGG-1::GFP foci) in seam cells (eLife, 2022-03; https://doi.org/10.7554/elife.67911) (doering2022nuclearhormonereceptor pages 8-11).

A 2024 Genes & Development study places NHR-49/MDT-15 as a signaling module that links lipid metabolic remodeling to HSF-1-dependent heat shock response and proteostasis, demonstrating that NHR-49 activation can be sufficient to improve proteostasis measures (sala2024nuclearreceptorsignaling pages 1-2, sala2024nuclearreceptorsignaling pages 7-8).

3.7 Neuronal physiology and pathogen avoidance behavior (2024 advance)

A 2024 Cells paper identifies a cell-autonomous neuronal role: loss of nhr-49 causes impaired pathogen lawn avoidance (PA14) associated with prolonged URX calcium transients after O2 upshift, and neuronal rescue in URX/AQR/PQR improves both behavior and calcium kinetics. This work links lipid homeostasis and neuronal excitability and demonstrates a direct neural implementation of nhr-49 function beyond intestinal metabolism (kwon2024regulatoroflipid pages 1-2, kwon2024regulatoroflipid pages 9-11).

4) Recent developments (prioritizing 2023–2024)

4.1 2023 authoritative synthesis (expert review)

Doering et al. (Frontiers in Physiology, 2023-08-14; https://doi.org/10.3389/fphys.2023.1241591) consolidates NHR-49 as a hub integrating lipid metabolism with stress resilience, immunity, and healthy aging, and highlights open questions including tissue-specific outputs and upstream inputs (including ligand-like regulation) (doering2023nuclearhormonereceptor pages 1-2).

4.2 2023 mechanism: glucose restriction longevity through NHR-49 and desaturases

Jeong et al. (Nature Communications, 2023-01; https://doi.org/10.1038/s41467-023-35952-z) positions NHR-49 in a whole-animal signaling chain linking glucose restriction → neuronal AMPK signaling → peripheral lipid remodeling, reporting that restoration of NHR-49 in either neurons or intestine can rescue glucose-restriction longevity in an nhr-49 mutant background, consistent with non-cell-autonomous signaling (jeong2023anewampk pages 9-10).

4.3 2024 mechanism: NHR-49/MDT-15 regulates proteostasis through HSF-1

Sala et al. (Genes & Development, 2024-05; https://doi.org/10.1101/gad.351829.124) reports a lipid–proteostasis coupling in which NHR-49/MDT-15 acts upstream of HSF-1, linking reproductive/metabolic cues to organismal stress resilience; it provides quantitative aggregate-reduction data (sala2024nuclearreceptorsignaling pages 7-8).

4.4 2024 mechanism: neuronal NHR-49 tunes O2-sensing neuron activity and immune behavior

Kwon et al. (Cells, 2024-06; https://doi.org/10.3390/cells13110978) provides a neuron-specific implementation: NHR-49 in URX/AQR/PQR is required for normal calcium dynamics and PA14 avoidance, and dietary oleic acid can rescue deficits (kwon2024regulatoroflipid pages 1-2, kwon2024regulatoroflipid pages 9-11).

5) Quantitative statistics and data points (from the extracted sources)

5.1 Proteostasis (2024)

In Sala et al. (2024-05), intestinal activation of NHR-49 reduced polyglutamine aggregation: Q35::mCherry aggregates were reduced by 30% at day 5 of adulthood in an NHR-49-activated condition (sala2024nuclearreceptorsignaling pages 7-8).

5.2 Neuronal experiments (2024)

Kwon et al. (2024-06) uses multiple quantitative readouts for URX calcium transients (peak amplitude, rise/decay times, AUC, repolarization durations) and reports that 300 µM oleic acid improved avoidance behavior and URX calcium kinetics; imaging trials with maximum ΔF/F0 < 300% were excluded per QC criteria (kwon2024regulatoroflipid pages 2-4, kwon2024regulatoroflipid pages 9-11).

5.3 Hypoxia survival and autophagy metrics (2022; still highly relevant and mechanistic)

Doering et al. (eLife, 2022-03) reports embryo-to-L4 survival after hypoxia and quantifies autophagy dependence. Example quantitative outcomes include:
- After 24 h at 0.5% O2, approximately 86% of WT embryos reached at least L4; after 48 h, approximately 44% of WT reached L4 (visual evidence in cropped figures) (doering2022nuclearhormonereceptor media de728d3f).
- Autophagy gene perturbations reduced survival, e.g. RNAi of bec-1 to 27% and atg-10 to 28% versus 79% for empty-vector control; multiple autophagy mutants fell in the 41–44% range under hypoxia (doering2022nuclearhormonereceptor pages 8-11).
These data support NHR-49 as a transcriptional regulator upstream of an autophagy module required for hypoxia tolerance (doering2022nuclearhormonereceptor pages 8-11).

5.4 Genome-wide expression thresholds (2012)

Pathare et al. (2012-04) reports microarray significance thresholds used to define NHR-49-regulated genes (absolute log2 ratio ≥ 0.848 and p ≤ 0.001) (pathare2012coordinateregulationof pages 1-2).

6) Current applications and real-world implementations

6.1 NHR-49 as a tool node for metabolic and stress biology in C. elegans

Because NHR-49 integrates lipid metabolism with stress resilience and aging, it is widely used as:
- A genetic node to test how interventions (dietary composition, fasting, glucose restriction) reprogram metabolism and stress resistance (doering2023nuclearhormonereceptor pages 1-2, jeong2023anewampk pages 9-10).
- A tissue-specific biology model (neurons vs intestine vs hypodermis) for dissecting cell-autonomous versus systemic lipid signaling mechanisms (kwon2024regulatoroflipid pages 1-2, sala2024nuclearreceptorsignaling pages 7-8, doering2022nuclearhormonereceptor pages 8-11).

6.2 Mechanism-guided intervention testing

Recent primary studies show NHR-49-dependent phenotypes are modifiable by defined nutritional manipulations:
- Oleic acid supplementation (300 µM) modifies neuronal physiology and PA14 avoidance in nhr-49 mutants, operationalizing lipid supplementation as a functional test of NHR-49-linked lipid dysfunction in neurons (kwon2024regulatoroflipid pages 2-4, kwon2024regulatoroflipid pages 9-11).
- In glucose restriction models, NHR-49 sits in a chain connecting dietary inputs to membrane lipid remodeling and longevity, making it a practical target for mechanism-driven dietary/genetic perturbation experiments (jeong2023anewampk pages 9-10).

7) Expert opinion and analysis (authoritative synthesis)

A consistent expert perspective, especially in the 2023 Frontiers review, is that NHR-49 should be annotated not merely as a “lipid metabolism regulator,” but as a systems integrator that:
1) couples lipid catabolism/desaturation programs to organismal stress-defense networks, and
2) produces tissue-specific outputs (intestinal metabolic remodeling; neuronal excitability control; hypoxia/autophagy survival) while potentially receiving upstream regulation by unknown ligand-like inputs or metabolic state signals (doering2023nuclearhormonereceptor pages 1-2).

Summary table (evidence map)

Category Key findings Best supporting sources
Identity/domains nhr-49 in Caenorhabditis elegans encodes NHR-49, an HNF4-like nuclear hormone receptor transcription factor functionally compared with mammalian HNF4α and PPARα; it has canonical DNA-binding and ligand-binding domains, and GOF mutations map to the LBD. (doering2023nuclearhormonereceptor pages 1-2, lee2016gainoffunctionallelesin pages 1-2)
Molecular function Sequence-specific nuclear receptor transcription factor that both activates and represses gene programs controlling fatty-acid metabolism; required for fasting and oxidative-stress transcriptional responses and works with MDT-15. Structural modeling supports likely small-molecule interaction via the LBD, but no definitive endogenous ligand is established. (doering2023nuclearhormonereceptor pages 1-2, lee2016gainoffunctionallelesin pages 1-2, hu2018thecaenorhabditiselegans pages 1-5)
Partners/cofactors Validated partners include MDT-15 as coactivator, NHR-80 for desaturase gene activation, and NHR-66 for repressive lipid-remodeling and sphingolipid programs; NHR-13 also contributes to desaturase regulation without confirmed direct physical interaction. Yeast two-hybrid using NHR-49-LBD recovered 24 independent cDNAs from 13 genes. (pathare2012coordinateregulationof pages 2-3, pathare2012coordinateregulationof pages 14-15)
Tissue/cellular localization Broadly expressed in multiple tissues, including intestine and neurons. Cell-specific rescue places key functions in URX/AQR/PQR body-cavity neurons for pathogen avoidance and calcium control, and in intestine for proteostasis and stress programs; hypoxia studies also tested rescue in hypodermis, neurons, and muscle. GOF substitutions did not alter measured subcellular localization. (lee2016gainoffunctionallelesin pages 1-2, kwon2024regulatoroflipid pages 1-2, sala2024nuclearreceptorsignaling pages 7-8, doering2022nuclearhormonereceptor pages 8-11)
Key pathways/targets Major outputs include mitochondrial and peroxisomal β-oxidation genes acs-2, cpt-5, ech-1; fatty-acid desaturases fat-5, fat-6, fat-7; sphingolipid and lipid-remodeling genes; glyoxylate cycle gene icl-1; lipid transport genes lbp-1, lbp-8; and stress or immune genes including fmo-2 and gst-4. It also supports autophagy-linked hypoxia adaptation and neuronal lipid homeostasis. (pathare2012coordinateregulationof pages 1-2, lee2016functionalcharacterizationof pages 22-26, pathare2012coordinateregulationof pages 2-3, hu2018thecaenorhabditiselegans pages 1-5, doering2022nuclearhormonereceptor pages 8-11)
Phenotypes Loss of nhr-49 causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology and function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection. GOF alleles are functionally distinct and can produce long-, short-, or normal-lifespan outcomes depending on allele. (pathare2012coordinateregulationof pages 1-2, lee2016gainoffunctionallelesin pages 1-2, hu2018thecaenorhabditiselegans pages 1-5, kwon2024regulatoroflipid pages 1-2)
Recent 2023-2024 developments 2023: review consolidates NHR-49 as a core stress-resilience and healthy-aging regulator; glucose-restriction longevity requires non-cell-autonomous PAQR-2/NHR-49/Δ9-desaturase signaling. 2024: NHR-49 and MDT-15 were shown to couple lipid homeostasis to HSF-1 proteostasis; neuronal NHR-49 in URX/AQR/PQR tunes calcium dynamics and PA14 avoidance; free long-chain fatty acids were proposed to activate NHR-49/80 signaling to initiate development. (doering2023nuclearhormonereceptor pages 1-2, sala2024nuclearreceptorsignaling pages 1-2, kwon2024regulatoroflipid pages 1-2, sala2024nuclearreceptorsignaling pages 7-8, jeong2023anewampk pages 9-10)
Quantitative data points Microarray cutoff: absolute log2 ratio at least 0.848 and p ≤ 0.001 for NHR-49-regulated genes. Oleic acid rescue: 300 µM OA improved avoidance and URX calcium kinetics. Calcium imaging: trials with max ΔF/F0 < 300% were excluded. Proteostasis: intestinal NHR-49 activation reduced Q35 aggregates by 30% at day 5 adulthood. Hypoxia: after 24 h at 0.5% O2, about 86% WT embryos reached L4; after 48 h, about 44% WT reached L4. Autophagy-pathway perturbations lowered hypoxia survival to 27–44% versus 79% EV control. (pathare2012coordinateregulationof pages 1-2, kwon2024regulatoroflipid pages 2-4, kwon2024regulatoroflipid pages 9-11, sala2024nuclearreceptorsignaling pages 7-8, doering2022nuclearhormonereceptor pages 8-11, doering2022nuclearhormonereceptor media de728d3f)

Table: This table summarizes verified identity, molecular function, pathways, localization, phenotypes, and recent 2023-2024 findings for C. elegans NHR-49/UniProt O45666. It provides a concise evidence map for functional annotation with supporting citation IDs.

Visual evidence (hypoxia survival/autophagy)

Cropped figure panels supporting the quantitative hypoxia survival and autophagy-foci conclusions are available from the eLife 2022 paper (doering2022nuclearhormonereceptor media de728d3f, doering2022nuclearhormonereceptor media 16c37f01, doering2022nuclearhormonereceptor media 19a845b3).

Evidence gaps / cautions for annotation

  • Direct ligand identification for NHR-49 remains unresolved in the extracted evidence; several studies support LBD importance and ligand-like regulation but do not conclusively establish a specific endogenous ligand-binding event (lee2016gainoffunctionallelesin pages 1-2, kwon2024regulatoroflipid pages 9-11).
  • Some classic early primary papers that originally defined fasting response targets are referenced indirectly in reviews/dissertations but were not fully extracted here; therefore, targets listed are limited to those explicitly supported in the retrieved evidence (doering2023nuclearhormonereceptor pages 1-2, pathare2012coordinateregulationof pages 2-3).

References

  1. (doering2023nuclearhormonereceptor pages 1-2): Kelsie R. S. Doering, Glafira Ermakova, and Stefan Taubert. Nuclear hormone receptor nhr-49 is an essential regulator of stress resilience and healthy aging in caenorhabditis elegans. Frontiers in Physiology, Aug 2023. URL: https://doi.org/10.3389/fphys.2023.1241591, doi:10.3389/fphys.2023.1241591. This article has 27 citations.

  2. (pathare2012coordinateregulationof pages 2-3): Pranali P. Pathare, Alex Lin, Karin E. Bornfeldt, Stefan Taubert, and Marc R. Van Gilst. Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genetics, 8:e1002645, Apr 2012. URL: https://doi.org/10.1371/journal.pgen.1002645, doi:10.1371/journal.pgen.1002645. This article has 139 citations and is from a domain leading peer-reviewed journal.

  3. (pathare2012coordinateregulationof pages 14-15): Pranali P. Pathare, Alex Lin, Karin E. Bornfeldt, Stefan Taubert, and Marc R. Van Gilst. Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genetics, 8:e1002645, Apr 2012. URL: https://doi.org/10.1371/journal.pgen.1002645, doi:10.1371/journal.pgen.1002645. This article has 139 citations and is from a domain leading peer-reviewed journal.

  4. (hu2018thecaenorhabditiselegans pages 1-5): Queenie Hu, Dayana R D’Amora, Lesley T MacNeil, Albertha J M Walhout, and Terrance J Kubiseski. The caenorhabditis elegans oxidative stress response requires the nhr-49 transcription factor. G3 Genes|Genomes|Genetics, 8:3857-3863, Dec 2018. URL: https://doi.org/10.1534/g3.118.200727, doi:10.1534/g3.118.200727. This article has 51 citations.

  5. (sala2024nuclearreceptorsignaling pages 1-2): Ambre J. Sala, Rogan A. Grant, Ghania Imran, Claire Morton, Renee M. Brielmann, Szymon Gorgoń, Jennifer Watts, Laura C. Bott, and Richard I. Morimoto. Nuclear receptor signaling via nhr-49/mdt-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues. Genes & Development, May 2024. URL: https://doi.org/10.1101/gad.351829.124, doi:10.1101/gad.351829.124. This article has 9 citations and is from a highest quality peer-reviewed journal.

  6. (lee2016gainoffunctionallelesin pages 1-2): Kayoung Lee, Grace Ying Shyen Goh, Marcus Andrew Wong, Tara Leah Klassen, and Stefan Taubert. Gain-of-function alleles in caenorhabditis elegans nuclear hormone receptor nhr-49 are functionally distinct. PLoS ONE, 11:e0162708, Sep 2016. URL: https://doi.org/10.1371/journal.pone.0162708, doi:10.1371/journal.pone.0162708. This article has 44 citations and is from a peer-reviewed journal.

  7. (kwon2024regulatoroflipid pages 9-11): Saebom Kwon, Kyu-Sang Park, and Kyoung-hye Yoon. Regulator of lipid metabolism nhr-49 mediates pathogen avoidance through precise control of neuronal activity. Cells, 13:978, Jun 2024. URL: https://doi.org/10.3390/cells13110978, doi:10.3390/cells13110978. This article has 3 citations.

  8. (kwon2024regulatoroflipid pages 1-2): Saebom Kwon, Kyu-Sang Park, and Kyoung-hye Yoon. Regulator of lipid metabolism nhr-49 mediates pathogen avoidance through precise control of neuronal activity. Cells, 13:978, Jun 2024. URL: https://doi.org/10.3390/cells13110978, doi:10.3390/cells13110978. This article has 3 citations.

  9. (sala2024nuclearreceptorsignaling pages 7-8): Ambre J. Sala, Rogan A. Grant, Ghania Imran, Claire Morton, Renee M. Brielmann, Szymon Gorgoń, Jennifer Watts, Laura C. Bott, and Richard I. Morimoto. Nuclear receptor signaling via nhr-49/mdt-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues. Genes & Development, May 2024. URL: https://doi.org/10.1101/gad.351829.124, doi:10.1101/gad.351829.124. This article has 9 citations and is from a highest quality peer-reviewed journal.

  10. (doering2022nuclearhormonereceptor pages 8-11): Kelsie RS Doering, Xuanjin Cheng, Luke Milburn, Ramesh Ratnappan, Arjumand Ghazi, Dana L Miller, and Stefan Taubert. Nuclear hormone receptor nhr-49 acts in parallel with hif-1 to promote hypoxia adaptation in caenorhabditis elegans. eLife, Mar 2022. URL: https://doi.org/10.7554/elife.67911, doi:10.7554/elife.67911. This article has 29 citations and is from a domain leading peer-reviewed journal.

  11. (pathare2012coordinateregulationof pages 1-2): Pranali P. Pathare, Alex Lin, Karin E. Bornfeldt, Stefan Taubert, and Marc R. Van Gilst. Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genetics, 8:e1002645, Apr 2012. URL: https://doi.org/10.1371/journal.pgen.1002645, doi:10.1371/journal.pgen.1002645. This article has 139 citations and is from a domain leading peer-reviewed journal.

  12. (jeong2023anewampk pages 9-10): Jin-Hyuck Jeong, Jun-Seok Han, Youngae Jung, Seung-Min Lee, So-Hyun Park, Mooncheol Park, Min-Gi Shin, Nami Kim, Mi Sun Kang, Seokho Kim, Kwang-Pyo Lee, Ki-Sun Kwon, Chun-A. Kim, Yong Ryoul Yang, Geum-Sook Hwang, and Eun-Soo Kwon. A new ampk isoform mediates glucose-restriction induced longevity non-cell autonomously by promoting membrane fluidity. Nature Communications, Jan 2023. URL: https://doi.org/10.1038/s41467-023-35952-z, doi:10.1038/s41467-023-35952-z. This article has 41 citations and is from a highest quality peer-reviewed journal.

  13. (kwon2024regulatoroflipid pages 2-4): Saebom Kwon, Kyu-Sang Park, and Kyoung-hye Yoon. Regulator of lipid metabolism nhr-49 mediates pathogen avoidance through precise control of neuronal activity. Cells, 13:978, Jun 2024. URL: https://doi.org/10.3390/cells13110978, doi:10.3390/cells13110978. This article has 3 citations.

  14. (doering2022nuclearhormonereceptor media de728d3f): Kelsie RS Doering, Xuanjin Cheng, Luke Milburn, Ramesh Ratnappan, Arjumand Ghazi, Dana L Miller, and Stefan Taubert. Nuclear hormone receptor nhr-49 acts in parallel with hif-1 to promote hypoxia adaptation in caenorhabditis elegans. eLife, Mar 2022. URL: https://doi.org/10.7554/elife.67911, doi:10.7554/elife.67911. This article has 29 citations and is from a domain leading peer-reviewed journal.

  15. (lee2016functionalcharacterizationof pages 22-26): Ka Young Lee. Functional characterization of gene regulation by nhr-49. ArXiv, Jan 2016. URL: https://doi.org/10.14288/1.0305709, doi:10.14288/1.0305709. This article has 0 citations.

  16. (doering2022nuclearhormonereceptor media 16c37f01): Kelsie RS Doering, Xuanjin Cheng, Luke Milburn, Ramesh Ratnappan, Arjumand Ghazi, Dana L Miller, and Stefan Taubert. Nuclear hormone receptor nhr-49 acts in parallel with hif-1 to promote hypoxia adaptation in caenorhabditis elegans. eLife, Mar 2022. URL: https://doi.org/10.7554/elife.67911, doi:10.7554/elife.67911. This article has 29 citations and is from a domain leading peer-reviewed journal.

  17. (doering2022nuclearhormonereceptor media 19a845b3): Kelsie RS Doering, Xuanjin Cheng, Luke Milburn, Ramesh Ratnappan, Arjumand Ghazi, Dana L Miller, and Stefan Taubert. Nuclear hormone receptor nhr-49 acts in parallel with hif-1 to promote hypoxia adaptation in caenorhabditis elegans. eLife, Mar 2022. URL: https://doi.org/10.7554/elife.67911, doi:10.7554/elife.67911. This article has 29 citations and is from a domain leading peer-reviewed journal.

Artifacts

Citations

  1. doering2023nuclearhormonereceptor pages 1-2
  2. pathare2012coordinateregulationof pages 2-3
  3. hu2018thecaenorhabditiselegans pages 1-5
  4. lee2016gainoffunctionallelesin pages 1-2
  5. kwon2024regulatoroflipid pages 9-11
  6. sala2024nuclearreceptorsignaling pages 7-8
  7. doering2022nuclearhormonereceptor pages 8-11
  8. jeong2023anewampk pages 9-10
  9. pathare2012coordinateregulationof pages 1-2
  10. pathare2012coordinateregulationof pages 14-15
  11. sala2024nuclearreceptorsignaling pages 1-2
  12. kwon2024regulatoroflipid pages 1-2
  13. kwon2024regulatoroflipid pages 2-4
  14. lee2016functionalcharacterizationof pages 22-26
  15. https://doi.org/10.3389/fphys.2023.1241591
  16. https://doi.org/10.1371/journal.pgen.1002645
  17. https://doi.org/10.1534/g3.118.200727
  18. https://doi.org/10.1371/journal.pone.0162708
  19. https://doi.org/10.3390/cells13110978
  20. https://doi.org/10.1101/gad.351829.124
  21. https://doi.org/10.7554/elife.67911
  22. https://doi.org/10.1038/s41467-023-35952-z
  23. https://doi.org/10.3389/fphys.2023.1241591,
  24. https://doi.org/10.1371/journal.pgen.1002645,
  25. https://doi.org/10.1534/g3.118.200727,
  26. https://doi.org/10.1101/gad.351829.124,
  27. https://doi.org/10.1371/journal.pone.0162708,
  28. https://doi.org/10.3390/cells13110978,
  29. https://doi.org/10.7554/elife.67911,
  30. https://doi.org/10.1038/s41467-023-35952-z,
  31. https://doi.org/10.14288/1.0305709,

📚 Additional Documentation

Notes

(nhr-49-notes.md)

nhr-49 Research Notes

Gene Overview

nhr-49 (K10C3.6) encodes a nuclear hormone receptor in C. elegans (UniProt: O45666), classified as an orphan receptor belonging to the HNF4 (hepatocyte nuclear factor 4) family PMID:15719061. NHR-49 is a central regulator of lipid metabolism, functioning analogously to mammalian PPARalpha in controlling fatty acid beta-oxidation and desaturation PMID:15719061. The protein contains a C4-type zinc finger DNA-binding domain (aa 8-83), a nuclear receptor ligand-binding domain (aa 157-422), and a 9aaTAD transactivation motif (aa 413-421). Four isoforms (a-d) are produced by alternative splicing. NHR-49 acts as a hub nuclear receptor that partners with distinct co-factors (NHR-80, NHR-66, NHR-13) to regulate separate branches of lipid metabolism PMID:22511885.

Core Pathway: LIPL-4 -> LBP-8 -> NHR-49/NHR-80

NHR-49 is a critical downstream component of the lysosome-to-nucleus retrograde lipid signaling pathway that promotes longevity. In this pathway, the lysosomal acid lipase LIPL-4 generates lipid signals including oleoylethanolamide (OEA), which are transported to the nucleus by the lipid chaperone LBP-8, where they activate the NHR-49/NHR-80 nuclear receptor heterodimer PMID:25554789.

Key details of NHR-49's role in this pathway:
- Both NHR-49 and NHR-80 are required for LIPL-4- and LBP-8-mediated longevity PMID:25554789
- NHR-49 does NOT directly bind OEA; rather, OEA binds NHR-80 directly (Kd ~7.8 uM) and NHR-49 functions as a co-factor PMID:25554789
- The NHR-49/NHR-80 heterodimer activates transcription of target genes including acs-2 (>15-fold increase in lipl-4 Tg animals) and lbp-8 itself, forming a positive feedback loop PMID:25554789
- The pathway is independent of dietary restriction PMID:25554789

Heterodimerization Partners

NHR-49 forms a homodimer and physically interacts with distinct partner NHRs to regulate separate metabolic programs PMID:22511885.

NHR-80: Fatty acid desaturation

  • NHR-49 and NHR-80 directly interact, demonstrated by GST pull-down assays and yeast two-hybrid PMID:22511885
  • The NHR-49/NHR-80 partnership regulates delta-9 desaturase genes (fat-5, fat-6, fat-7) PMID:22511885
  • Loss of NHR-80 reduces lifespan to 13.19+/-0.38 days vs. 17.35+/-0.34 days in wild-type PMID:22511885
  • nhr-80;nhr-13 double mutants have lifespan (12.29+/-0.37 days) approaching nhr-49 mutant lifespan (9.52+/-0.23 days) PMID:22511885
  • Both NHR-49 and NHR-80 are derived from the same HNF4 ancestral gene PMID:16839188

NHR-66: Sphingolipid breakdown and lipid remodeling

  • NHR-49 partners with NHR-66 to repress genes involved in sphingolipid processing and lipid remodeling PMID:22511885
  • Direct physical interaction confirmed by GST pull-down PMID:22511885
  • NHR-66 does not contribute to the lifespan phenotype (nhr-66 lifespan: 17.16+/-0.41 days, similar to wild-type) PMID:22511885

NHR-13: Fatty acid desaturation

  • NHR-13 has a similar gene expression profile to NHR-80 regarding desaturase regulation PMID:22511885
  • NHR-13 did not bind NHR-49 directly in vitro pull-down assays, suggesting indirect interaction or requirement for additional factors PMID:22511885
  • nhr-13 mutants have shortened lifespan (14.17+/-0.4 days) PMID:22511885

Additional interactions

  • May interact with NHR-22, NHR-79, NHR-105, NHR-256 (UniProt, based on PMID:22511885)
  • Physical interactions detected with MDT-15, NHR-13, NHR-181, NHR-19, NHR-20, NHR-234, NHR-76 (IntAct database, UniProt)

Fatty Acid Metabolism (fat-5/6/7, acs-2 regulation)

NHR-49 regulates two distinct branches of fatty acid metabolism:

Branch 1: Beta-oxidation (fat consumption)

  • NHR-49 positively regulates acs-2 (acyl-CoA synthetase) and ech-1 (enoyl-CoA hydratase), which promote mitochondrial beta-oxidation PMID:15719061
  • acs-2 expression is reduced in nhr-49(nr2041) mutants; ectopic acs-2 expression rescues the high-fat phenotype PMID:15719061
  • In germline-less animals, NHR-49 upregulates 7 mitochondrial beta-oxidation genes: acs-2, acs-22, cpt-2, cpt-5, acdh-11, ech-1.1, and hacd-1 PMID:25474470

Branch 2: Fatty acid desaturation (fatty acid composition)

  • NHR-49 activates expression of delta-9 desaturases fat-5, fat-6, fat-7, acting through partners NHR-80 and NHR-13 [PMID:15719061, PMID:22511885]
  • fat-7 is the primary target; fat-7 RNAi phenocopies the shortened lifespan of nhr-49(nr2041) PMID:15719061
  • NHR-49 may form a negative feedback loop with fat-7: NHR-49 stimulates fat-7 and acs-2 expression, and fat-7 indirectly inhibits acs-2 and other beta-oxidation genes (UniProt, PMID:15719061)

ACDH-11 and heat adaptation

  • ACDH-11 (acyl-CoA dehydrogenase) sequesters medium-chain fatty acids (C11, C12). Loss of acdh-11 releases these fatty acids, which activate fat-7 expression through NHR-49 PMID:25981666
  • NHR-49 RNAi eliminates the effect of C11 or C12 chain fatty acids in activating fat-7 and blocks fat-7 overexpression in acdh-11 mutants (UniProt, PMID:25981666)

Longevity Function

NHR-49 impacts lifespan through multiple mechanisms:

Direct lifespan effects

  • nhr-49(nr2041) deletion mutants have drastically shortened lifespan (~41% reduction vs. wild-type) [PMID:15719061, PMID:25554789]
  • The shortened lifespan correlates with impaired fat-7 expression and excess saturated fat PMID:22511885
  • NHR-49 overexpression in fertile animals extends lifespan by ~15% PMID:25474470

Germline-mediated longevity

  • NHR-49 is essential for the longevity of germline-less (glp-1) animals; nhr-49 RNAi completely abrogates glp-1 longevity PMID:25474470
  • Upon germline removal, NHR-49 is transcriptionally upregulated by DAF-16/FOXO and TCER-1/TCERG1 in somatic tissues PMID:25474470
  • NHR-49 is NOT required for daf-2/insulin-pathway longevity PMID:25474470
  • NHR-49 is NOT required for mitochondrial electron transport chain mutant longevity (cyc-1, cco-1 RNAi) PMID:25474470

LIPL-4/LBP-8 pathway longevity

  • Required for LIPL-4 and LBP-8 overexpression-mediated lifespan extension PMID:25554789
  • Functions together with NHR-80 as the downstream effector of lysosomal lipid signaling PMID:25554789

Mit mutant longevity

  • NHR-49 is required for lifespan extension of isp-1(qm150) Mit mutants PMID:24107417
  • Not required for RNAi-induced Mit mutants (nuo-1, ucr-1, cyc-1, cco-3) PMID:24107417

Hypoxia Adaptation

NHR-49 plays a critical role in adaptation to low oxygen environments, acting in parallel with HIF-1 [PMID:35285794, Doering et al. 2022]:
- nhr-49 mutants show severe hypoxia sensitivity: only 25% of embryos develop to L4 stage in 0.5% O2 vs. 86% in wild-type (UniProt, PMID:35285794)
- In a hif-1 mutant background, nhr-49 loss is nearly lethal under hypoxia (<2% survival to L4) (UniProt, PMID:35285794)
- NHR-49 activates expression of acs-2, autophagy-related genes, and autophagosome formation during hypoxia, independent of HIF-1 (UniProt, PMID:35285794)
- NHR-49 activates the detoxification gene fmo-2 (flavin mono-oxygenase), acting in parallel with HIF-1 during hypoxia (UniProt, PMID:35285794)
- NHR-49 acts in multiple somatic tissues, probably cell non-autonomously, in regulating hypoxia response (UniProt, PMID:35285794)
- nhr-49 mutants are unaffected by hydrogen sulfide (UniProt, PMID:35285794)
- Hypoxia exposure (0.5% oxygen) triggers nhr-49-dependent responses (UniProt, PMID:35285794)

Mediator Complex Interaction (MDT-15)

MDT-15, a subunit of the C. elegans Mediator complex, acts as a transcriptional coactivator for NHR-49 PMID:16651656:
- MDT-15 is required for fasting-induced expression of NHR-49 target genes in vivo PMID:16651656
- MDT-15 is also required for fasting-independent expression of NHR-49 targets including fat-5 and fat-7 PMID:16651656
- MDT-15 additionally regulates NHR-49-independent targets, such as fat-6, suggesting it integrates multiple regulatory inputs PMID:16651656
- mdt-15 knockdown causes dramatically decreased unsaturated fatty acids and pleiotropic phenotypes (short lifespan, sterility, uncoordinated locomotion, morphological defects) PMID:16651656
- Physical interaction between NHR-49 and MDT-15 confirmed (IntAct, UniProt)

PKG and Lysosomal Lipid Metabolism

During short-term fasting, NHR-49 acts in the intestine to regulate lysosomal lipid accumulation in coordination with EGL-4/PKG signaling from sensory neurons PMID:24854345:
- NHR-49 inhibits lysosomal lipid accumulation during fasting via activation of IPLA-2 (intracellular phospholipase A2) in the cytoplasm and hydrolases in lysosomes PMID:24854345
- This fasting-induced lysosomal lipid accumulation is independent of autophagy and RAB-7-mediated endocytosis PMID:24854345

Transgenerational Epigenetic Regulation

NHR-49 is required for transgenerational inheritance of high-fat-diet (HFD)-induced lipid accumulation PMID:35140229:
- NHR-49, NHR-80, SBP-1/SREBP, and DAF-16/FOXO are all required for transgenerational epigenetic inheritance of obesogenic lipid accumulation PMID:35140229
- NHR-49 and NHR-80 function as executors (effectors), not transmitters, of heritable lipid metabolic memory PMID:35140229
- The transgenerational signal is mediated by histone H3K4me3 modification PMID:35140229
- Delta-9 desaturases (fat-5, fat-6, fat-7) are also required for the transgenerational lipid phenotype PMID:35140229

Subcellular Localization

  • NHR-49 localizes to both nucleus and cytoplasm, with highest expression in intestinal cells PMID:25474470
  • Expressed in head, intestine, and hypodermal seam cells (UniProt, PMID:35285794)
  • Also expressed in neurons, muscle, and hypodermis PMID:25474470
  • NHR-49::GFP is visible throughout embryonic and larval development PMID:25474470
  • Nuclear localization predicted by PROSITE NR DBD domain (UniProt)

Regulation

  • Germline removal: NHR-49 mRNA and protein levels are elevated upon germline ablation, dependent on DAF-16/FOXO and TCER-1/TCERG1 PMID:25474470
  • In fertile animals, nhr-49 expression is DAF-16 and TCER-1 independent PMID:25474470
  • Fasting: NHR-49 coordinates expression of fatty acid metabolic genes during feeding and in response to fasting PMID:16651656
  • Hypoxia: Exposure to 0.5% oxygen triggers NHR-49-dependent transcriptional responses (UniProt, PMID:35285794)
  • NHR-49 is an orphan receptor; no endogenous ligand has been identified [PMID:25981666, UniProt]

Disruption Phenotype

nhr-49(nr2041) mutants (893 bp deletion) exhibit:
- Elevated fat storage: Increased Nile Red staining; high-fat phenotype due to reduced beta-oxidation gene expression PMID:15719061
- Shortened lifespan: ~41% reduction compared to wild-type; lifespan of 9.52+/-0.23 days vs. 17.35+/-0.34 at 20C [PMID:15719061, PMID:22511885]
- Altered fatty acid composition: Increased ratio of stearic acid to oleic acid (C18:0/C18:1n9 ratio of 3.74+/-0.33 vs. 0.98+/-0.06 in wild-type) [PMID:15719061, PMID:22511885]
- Vacuole formation and germline necrosis: Widespread vacuoles in intestine and gonadal collapse PMID:15719061
- Abnormal mitochondrial morphology: ~25% of intestinal mitochondria show irregular shape with more turns; reduced oxygen consumption (5.22 vs. 9.625 pmoles/min/worm in wild-type); reduced beta-oxidation PMID:22511885
- Hypoxia sensitivity: Only 25% embryo survival to L4 under 0.5% O2; L1 larvae survival reduced to 19% vs. 95% in wild-type (UniProt, PMID:35285794)
- Mild developmental delay: Slower larval growth (UniProt, PMID:35285794)
- Suppressed glp-1 longevity: Completely abolishes the lifespan extension of germline-less animals PMID:25474470

Mitochondrial Function

NHR-49 is important for maintaining mitochondrial morphology and function PMID:22511885:
- nhr-49 mutants have reduced basal oxygen consumption rates (5.22 pmoles/min/worm vs. 9.625 in wild-type) PMID:22511885
- Reduced beta-oxidation measured by radiolabeled palmitate assay (0.56 vs. 1.29 pmole/min/ug protein in wild-type) PMID:22511885
- NHR-49 maintains mitochondrial morphology via multiple pathways including NHR-66 and NHR-80 dependent regulation PMID:22511885

📄 View Raw YAML

 
id: O45666
gene_symbol: nhr-49
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  NHR-49 is an orphan nuclear hormone receptor of the HNF4 family that serves
  as a central transcriptional regulator of lipid metabolism in C. elegans,
  functionally analogous to mammalian PPARalpha. NHR-49 controls two major
  metabolic branches: (1) fatty acid beta-oxidation, by promoting expression of
  acs-2, ech-1, cpt-5, and other mitochondrial beta-oxidation genes, and (2)
  fatty acid desaturation, by activating delta-9 desaturases fat-5 and fat-7
  (with modest effects on fat-6). NHR-49 operates through distinct
  heterodimeric partnerships: NHR-49/NHR-80 regulates desaturation genes,
  NHR-49/NHR-66 represses sphingolipid and lipid remodeling genes, and
  NHR-49/NHR-13 also contributes to desaturase regulation. NHR-49 also
  interacts with the Mediator subunit MDT-15 as a transcriptional coactivator.
  Loss of nhr-49 causes dramatically shortened lifespan (~41% reduction),
  increased fat storage, and altered fatty acid composition with elevated
  stearic-to-oleic acid ratio. NHR-49 is required for LIPL-4/LBP-8-mediated
  longevity signaling (acting as a cofactor with NHR-80, which is the direct
  OEA receptor), for germline-loss-mediated longevity (where it is
  transcriptionally upregulated by DAF-16 and TCER-1), and for hypoxia
  adaptation in parallel with HIF-1. NHR-49 also participates in
  transgenerational epigenetic inheritance of lipid accumulation from high-fat
  diet, functioning as an executor but not a transmitter of heritable memory.
  NHR-49 is expressed broadly in somatic tissues including intestine, neurons,
  hypodermis, and muscle, localizing to both nucleus and cytoplasm. It is an
  orphan receptor with no confirmed endogenous ligand; NHR-49 does not bind
  oleoylethanolamide (OEA), unlike its partner NHR-80.
alternative_products:
- name: c
  id: O45666-1
- name: a
  id: O45666-2
  sequence_note: VSP_015670
- name: b
  id: O45666-3
  sequence_note: VSP_015670, VSP_015672
- name: d
  id: O45666-4
  sequence_note: VSP_015671
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NHR-49 is a nuclear hormone receptor with a predicted nuclear localization
      based on its DNA-binding domain (PROSITE-ProRule:PRU00407). Multiple
      experimental studies confirm nuclear localization: NHR-49::GFP is visible
      in nuclei of neurons, muscle, hypodermis, and intestinal cells
      (PMID:25474470), and nuclear localization is increased upon germline
      removal. The IBA annotation from phylogenetic inference is fully consistent
      with these experimental data.
    action: ACCEPT
    reason: >-
      Nuclear localization is a core feature of NHR-49 as a nuclear hormone
      receptor transcription factor. IDA evidence (PMID:25474470) directly
      confirms this IBA annotation. NHR-49::GFP localizes to nuclei in multiple
      somatic tissues. Falcon deep research notes NHR-49 is broadly expressed
      in multiple tissues including intestine and neurons.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25474470
      supporting_text: >-
        NHR-49::GFP is visible in the cytoplasm and nuclei of neurons (E),
        muscle (F), hypodermis (G) and intestinal cells (H).
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        Broadly expressed in multiple tissues, including **intestine** and **neurons**

- 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: >-
      NHR-49 contains a conserved zinc-finger DNA-binding domain (HNF4-like,
      InterPro IPR049636) and functions as a transcription factor that activates
      target gene promoters including acs-2, fat-5, fat-7, and fmo-2
      (PMID:15719061, PMID:22511885, PMID:35285794). The IBA annotation from
      phylogenetic inference is consistent with NHR-49 being a nuclear receptor
      that binds DNA in a sequence-specific manner, although direct
      cis-regulatory binding assays (e.g., ChIP) have not been published
      specifically for NHR-49.
    action: ACCEPT
    reason: >-
      NHR-49 has a well-characterized zinc-finger DNA-binding domain and
      controls transcription of specific target genes. The IBA annotation is
      phylogenetically sound for this HNF4 family member. It is reasonable
      that NHR-49 binds cis-regulatory regions of its target gene promoters
      to achieve the highly specific transcriptional effects documented across
      multiple studies. Falcon deep research describes NHR-49 as a
      sequence-specific transcription factor that both activates and represses
      metabolic gene programs.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        Our screen revealed that deletion of nhr-49 significantly altered the
        expression of 13 genes, including six genes predicted to be involved
        in fatty acid β-oxidation, three genes involved in fatty acid
        desaturation
    - reference_id: PMID:22511885
      supporting_text: >-
        We show that NHR-49 regulates distinct subsets of its target genes by
        partnering with at least two other distinct nuclear receptors
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        NHR-49 acts as a **transcriptional regulator** that can both **activate** and **repress** metabolic gene programs

- term:
    id: GO:0004879
    label: nuclear receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NHR-49 is an established member of the nuclear hormone receptor family,
      containing both a zinc-finger DNA-binding domain and a ligand-binding
      domain (NR LBD, PROSITE PRU01189). It is classified as an orphan nuclear
      receptor, as no endogenous ligand has been confirmed (PMID:25554789
      showed NHR-49 does not bind OEA). NHR-49 functions as a
      ligand-independent or orphan transcription factor that regulates lipid
      metabolism genes (PMID:15719061, PMID:22511885).
    action: ACCEPT
    reason: >-
      Nuclear receptor activity is a core molecular function of NHR-49. It has
      the characteristic NHR domain architecture (DBD + LBD) and functions as
      a transcriptional regulator through DNA binding and partner interactions.
      The IBA annotation accurately captures this fundamental function. Falcon
      deep research independently confirms NHR-49 as a sequence-specific nuclear
      receptor transcription factor functionally comparable to mammalian PPARalpha
      and HNF4alpha, and notes that despite a functionally important ligand-binding
      domain, no definitive endogenous ligand is established (orphan receptor).
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms
        with elevated fat content and shortened life span
    - reference_id: PMID:25554789
      supporting_text: >-
        no binding was detected between NHR-49 and OEA or OEA analogue
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        NHR-49 is a sequence-specific transcription factor of the nuclear receptor superfamily
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        a definitive endogenous ligand for NHR-49 is not established

- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      NHR-49 is a transcription factor that regulates expression of numerous
      target genes involved in fatty acid beta-oxidation and desaturation
      (PMID:15719061), sphingolipid processing (PMID:22511885), hypoxia
      response (PMID:35285794), and autophagy genes. It works with the
      Mediator subunit MDT-15 as a transcriptional coactivator
      (PMID:16651656), placing it squarely in the Pol II transcription
      regulatory machinery.
    action: ACCEPT
    reason: >-
      Regulation of Pol II transcription is a core biological process for
      NHR-49. Multiple studies demonstrate its role in activating and
      repressing transcription of specific gene sets through partnerships
      with other NHRs and with the Mediator complex. The IBA annotation is
      well supported. Falcon deep research reinforces the central role of
      MDT-15 (Mediator subunit) as a critical co-regulator across NHR-49
      transcriptional outputs in both metabolism and stress programs.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:16651656
      supporting_text: >-
        we report the identification of MDT-15, a subunit of the C. elegans
        Mediator complex, as an NHR-49-interacting protein and transcriptional
        coactivator
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49 is extensively involved in the control of fatty acid metabolism,
        with a pronounced role in the promotion of mitochondrial β-oxidation
        and fatty acid desaturation
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        MDT-15 (Mediator subunit)** as a critical co-regulator for NHR-49-driven transcriptional outputs

- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      There is no direct experimental evidence that NHR-49 plays a role in
      cell differentiation in C. elegans. The original Van Gilst 2005 study
      explicitly noted that nhr-49 deletion did not noticeably affect
      development or fertility (PMID:15719061). NHR-49 is primarily a
      metabolic regulator. The IBA annotation may reflect a conserved role
      in HNF4 family members in vertebrates (where HNF4alpha has roles in
      liver and intestinal differentiation), but this function has not been
      demonstrated for nhr-49 in C. elegans.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While HNF4 family members in vertebrates play roles in cell
      differentiation, NHR-49 in C. elegans is characterized as a metabolic
      regulator with no documented role in cell differentiation. Loss of
      nhr-49 does not affect development or fertility (PMID:15719061). This
      IBA annotation likely over-extrapolates from vertebrate HNF4 functions
      that are not conserved in the nematode lineage. Falcon deep research
      consistently characterizes NHR-49 as a metabolic and stress-resilience
      regulator with no documented role in cell differentiation, supporting
      this over-annotation call.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        Although nhr-49 deletion did not noticeably affect development or
        fertility, nhr-49(nr2041) worms experienced rapid decline in function
        beginning around day 3 of adulthood
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        NHR-49 coordinates transcriptional programs that balance lipid catabolism

- 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: >-
      This IEA annotation from InterPro domain mapping duplicates the IBA
      annotation for the same term. NHR-49 contains a HNF4-like DNA-binding
      domain (InterPro IPR049636) and a nuclear receptor zinc finger
      (IPR001628), consistent with sequence-specific DNA binding at Pol II
      cis-regulatory regions.
    action: ACCEPT
    reason: >-
      The InterPro-based IEA annotation is consistent with NHR-49 domain
      architecture and its demonstrated function as a transcription factor.
      It is broader than the IBA annotation for the same term, but both are
      acceptable annotations for the same GO term from different evidence
      sources.
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        Our screen revealed that deletion of nhr-49 significantly altered the
        expression of 13 genes, including six genes predicted to be involved
        in fatty acid β-oxidation, three genes involved in fatty acid
        desaturation

- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-49 is a well-established DNA-binding transcription factor that
      regulates expression of multiple target genes. However, the more
      specific term GO:0004879 (nuclear receptor activity) is already
      annotated via IBA and better captures the molecular function. This
      broader IEA term is not wrong but is less informative than the more
      specific nuclear receptor activity annotation.
    action: ACCEPT
    reason: >-
      While GO:0004879 (nuclear receptor activity) is more specific and
      already annotated, this broader IEA annotation from InterPro is not
      incorrect. It is acceptable to retain both a broader IEA and a more
      specific IBA annotation for the same gene.
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49 is extensively involved in the control of fatty acid metabolism,
        with a pronounced role in the promotion of mitochondrial β-oxidation
        and fatty acid desaturation

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      This IEA annotation from UniProt subcellular location mapping is
      consistent with NHR-49 nuclear localization confirmed by IDA evidence
      (PMID:25474470) and IBA. UniProt lists nuclear localization based on
      PROSITE-ProRule:PRU00407.
    action: ACCEPT
    reason: >-
      The IEA annotation is correct and supported by multiple lines of
      experimental evidence for nuclear localization. It duplicates the IBA
      and IDA annotations for the same term but from a different evidence
      source, which is acceptable.
    supported_by:
    - reference_id: PMID:25474470
      supporting_text: >-
        NHR-49::GFP is visible in the cytoplasm and nuclei of neurons (E),
        muscle (F), hypodermis (G) and intestinal cells (H).

- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      This IEA annotation is a broader parent term of GO:0006357 (regulation
      of transcription by RNA polymerase II), which is annotated via IBA.
      NHR-49 clearly regulates DNA-templated transcription of numerous
      target genes (PMID:15719061, PMID:22511885, PMID:16651656).
    action: ACCEPT
    reason: >-
      The annotation is correct. While it is broader than the IBA annotation
      for Pol II-specific regulation, it is not incorrect to retain both.
      NHR-49 is fundamentally a transcriptional regulator.
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        Our screen revealed that deletion of nhr-49 significantly altered the
        expression of 13 genes

- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-49 contains two NR C4-type zinc finger motifs (residues 11-31 and
      47-71) within its DNA-binding domain, as annotated in UniProt based on
      PROSITE-ProRule:PRU00407. Zinc coordination is essential for the
      structural integrity of the nuclear receptor DNA-binding domain.
    action: ACCEPT
    reason: >-
      The zinc ion binding annotation is correct based on the well-characterized
      C4-type zinc finger motifs in the NHR-49 DNA-binding domain. This is a
      structural feature inherent to all nuclear hormone receptors.
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49(nr2041), which harbors a deletion in the nhr-49 gene
        encompassing part of the DNA binding domain and more than half of
        the ligand binding domain

- term:
    id: GO:0030522
    label: intracellular receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: >-
      NHR-49 is an intracellular (nuclear) receptor that transduces signals
      by regulating transcription. Although it is an orphan receptor with no
      confirmed endogenous ligand, NHR-49 functions as a cofactor with NHR-80
      in the LIPL-4/LBP-8/OEA lysosome-to-nucleus signaling pathway
      (PMID:25554789) and responds to germline signals via DAF-16/TCER-1
      upregulation (PMID:25474470). The annotation derived from logical
      inference based on the nuclear receptor activity annotation is
      reasonable.
    action: ACCEPT
    reason: >-
      NHR-49 participates in intracellular receptor signaling as a nuclear
      receptor transcription factor. Even though it is orphan (no direct
      ligand), it functions within signaling pathways that regulate its
      activity and target gene expression. The IEA annotation from logical
      inference is appropriate. Falcon deep research reaffirms NHR-49 as an
      orphan nuclear receptor whose ligand-binding domain is functionally
      important but for which no definitive endogenous ligand is established.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        Nuclear hormone receptors nhr-49 and nhr-80, previously demonstrated
        to physically interact (10), were both required for lipl-4–and
        lbp-8–mediated longevity
    - reference_id: PMID:25474470
      supporting_text: >-
        NHR-49 is transcriptionally up-regulated by DAF-16 and TCER-1 in
        the soma upon germline removal
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        a definitive endogenous ligand for NHR-49 is not established

- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      NHR-49 contains a conserved HNF4-like DNA-binding domain with two C4-type
      zinc fingers. This IEA annotation is a parent of the more specific
      GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA
      binding) already annotated. It is correct but less specific.
    action: ACCEPT
    reason: >-
      The annotation is correct. NHR-49 binds DNA in a sequence-specific
      manner through its zinc finger DNA-binding domain. While more specific
      annotations exist, the IEA from InterPro is not incorrect.
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49 is extensively involved in the control of fatty acid metabolism,
        with a pronounced role in the promotion of mitochondrial β-oxidation
        and fatty acid desaturation

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14704431
  review:
    summary: >-
      PMID:14704431 (Li et al. 2004) reports a high-throughput yeast two-hybrid
      interactome mapping study for C. elegans. NHR-49 was identified as an
      interactor in this screen. However, the generic term protein binding
      is uninformative. From subsequent focused studies, NHR-49 has been shown
      to physically interact with specific partners including NHR-80, NHR-66,
      NHR-13, and MDT-15 (PMID:22511885, PMID:16651656). A more specific
      term such as DNA-binding transcription factor binding (GO:0140297) would
      be more appropriate.
    action: MODIFY
    reason: >-
      Protein binding is too vague for NHR-49, whose protein interactions are
      well characterized. The high-throughput Y2H screen identified
      interactions that are better captured by more specific terms. NHR-49
      interacts with other transcription factors (NHR-80, NHR-66, NHR-13) and
      the Mediator coactivator MDT-15. GO:0140297 (DNA-binding transcription
      factor binding) better describes these interactions.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:22511885
      supporting_text: >-
        We show that NHR-49 regulates distinct subsets of its target genes by
        partnering with at least two other distinct nuclear receptors
    - reference_id: PMID:16651656
      supporting_text: >-
        we report the identification of MDT-15, a subunit of the C. elegans
        Mediator complex, as an NHR-49-interacting protein and transcriptional
        coactivator

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16651656
  review:
    summary: >-
      PMID:16651656 (Taubert et al. 2006) identified MDT-15, a Mediator
      subunit, as a physical interacting partner and transcriptional
      coactivator of NHR-49. The interaction was shown through yeast
      two-hybrid and functional studies. The generic protein binding term
      fails to capture this specific and functionally important interaction
      with the Mediator complex.
    action: MODIFY
    reason: >-
      The interaction between NHR-49 and MDT-15 (Mediator subunit) represents
      a transcription factor-coactivator interaction. GO:0140297 (DNA-binding
      transcription factor binding) is more appropriate, as MDT-15 is itself a
      transcriptional coregulator.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:16651656
      supporting_text: >-
        we report the identification of MDT-15, a subunit of the C. elegans
        Mediator complex, as an NHR-49-interacting protein and transcriptional
        coactivator. Knockdown of mdt-15 by RNA interference (RNAi) prevented
        fasting-induced mRNA accumulation of NHR-49 targets in vivo

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19123269
  review:
    summary: >-
      PMID:19123269 (Simonis et al. 2009) is a high-throughput yeast
      two-hybrid interactome mapping study that provides expanded coverage of
      C. elegans protein-protein interactions. Similar to PMID:14704431, the
      generic protein binding term is uninformative for NHR-49, whose specific
      interaction partners are well characterized.
    action: MODIFY
    reason: >-
      As with the other protein binding annotations, a more specific term is
      warranted. NHR-49 interacts with other NHRs and the Mediator complex.
      GO:0140297 (DNA-binding transcription factor binding) better describes
      the interactions detected.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:22511885
      supporting_text: >-
        We show that NHR-49 regulates distinct subsets of its target genes by
        partnering with at least two other distinct nuclear receptors

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23791784
  review:
    summary: >-
      PMID:23791784 (Reece-Hoyes et al. 2013) characterized transcription
      factor network rewiring in C. elegans through systematic Y2H and other
      interaction assays. The study found that even highly similar TFs often
      have different interaction partners. For NHR-49, this provides network
      context but the generic protein binding annotation is too vague.
    action: MODIFY
    reason: >-
      The protein binding term is too generic for NHR-49. The interactions
      detected in this TF network study are primarily TF-TF interactions.
      GO:0140297 (DNA-binding transcription factor binding) is more specific
      and appropriate.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
    supported_by:
    - reference_id: PMID:23791784
      supporting_text: >-
        we comprehensively characterize such network rewiring for C. elegans
        transcription factors (TFs) within and across four newly delineated
        molecular networks

- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:22511885
  review:
    summary: >-
      PMID:22511885 (Pathare et al. 2012) demonstrated that NHR-49 physically
      interacts with multiple nuclear hormone receptors including NHR-80,
      NHR-66, NHR-13, NHR-22, NHR-79, NHR-105, and NHR-256, forming both
      homodimers and heterodimers. Direct physical interactions were confirmed
      for NHR-49/NHR-80 and NHR-49/NHR-66 by yeast two-hybrid and functional
      studies. This term accurately captures NHR-49 binding to other
      DNA-binding transcription factors.
    action: ACCEPT
    reason: >-
      This annotation accurately describes the well-characterized physical
      interactions between NHR-49 and other NHRs (NHR-80, NHR-66, NHR-13).
      The term is specific and informative, directly supported by the
      referenced study. Falcon deep research independently summarizes the
      context-dependent NHR partnerships (NHR-80 for desaturase genes, NHR-66
      for sphingolipid/lipid remodeling genes).
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:22511885
      supporting_text: >-
        We show that NHR-49 regulates distinct subsets of its target genes by
        partnering with at least two other distinct nuclear receptors
    - reference_id: PMID:22511885
      supporting_text: >-
        Gene expression profiles suggest that NHR-49 partners with NHR-66 to
        regulate sphingolipid and lipid remodeling genes and with NHR-80 to
        regulate genes involved in fatty acid desaturation
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        NHR-49 was shown to regulate distinct gene subsets via **partnerships with other NHRs**
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        **NHR-80**: linked to regulation of **fatty-acid desaturase** genes.

- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:24854345
  review:
    summary: >-
      PMID:24854345 (Huang et al. 2014) showed that NHR-49 acts in the
      intestine during short-term fasting to regulate lysosomal lipid
      accumulation, coordinating with PKG/EGL-4 signaling. NHR-49 activates
      expression of IPLA-2 and other hydrolases in response to fasting. The
      positive regulation of transcription annotation is consistent with
      NHR-49 activating target gene expression in this context.
    action: ACCEPT
    reason: >-
      NHR-49 positively regulates transcription of target genes including
      acs-2, fat-5, fat-7, fmo-2, and genes involved in fasting responses.
      The IMP evidence from the fasting study supports this annotation,
      though the annotation captures a general function rather than
      the specific fasting context.
    supported_by:
    - reference_id: PMID:24854345
      supporting_text: >-
        NHR-49 acts in intestine to inhibit lipids accumulation via activation
        of IPLA-2

- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IGI
  original_reference_id: PMID:24107417
  review:
    summary: >-
      PMID:24107417 (Khan et al. 2013) identified NHR-49 among transcription
      factors whose RNAi knockdown affected development, stress response, or
      fecundity of isp-1 mitochondrial (Mit) mutants. The study examined
      lifespan in Mit mutants. NHR-49 is listed alongside HIF-1 and other TFs
      that affect Mit mutant lifespan. This is consistent with NHR-49 having
      a role in lifespan determination, particularly in the context of
      mitochondrial function.
    action: ACCEPT
    reason: >-
      NHR-49 has a well-established role in determination of adult lifespan.
      Loss of nhr-49 causes ~41% reduction in lifespan (PMID:15719061,
      PMID:16839188), and it is required for longevity mediated by germline
      loss (PMID:25474470) and LIPL-4 signaling (PMID:25554789). The IGI
      evidence from the Mit mutant context adds another dimension to this
      core function.
    supported_by:
    - reference_id: PMID:24107417
      supporting_text: >-
        Seven of these transcription factors--AHA-1, CEH-18, HIF-1, JUN-1,
        NHR-27, NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein
        TAF-4--were also essential for isp-1 life extension.
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49(nr2041) worms lived only 6–8 d as adults, significantly
        shorter than the 15 to 18-d life span of N2 wild-type (WT) animals

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25474470
  review:
    summary: >-
      PMID:25474470 (Ratnappan et al. 2014) directly demonstrated NHR-49::GFP
      localization to both nuclei and cytoplasm in adult somatic tissues,
      with highest expression in intestinal cells. Nuclear localization was
      especially prominent upon germline removal.
    action: ACCEPT
    reason: >-
      Direct experimental evidence using NHR-49::GFP fusion protein confirms
      nuclear localization in multiple tissues. This is a core annotation for
      a nuclear hormone receptor.
    supported_by:
    - reference_id: PMID:25474470
      supporting_text: >-
        In adults, it was visible in all somatic tissues (Fig

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:25474470
  review:
    summary: >-
      PMID:25474470 (Ratnappan et al. 2014) showed NHR-49::GFP localization
      to both nuclei and cytoplasm in adult somatic tissues. Cytoplasmic
      localization was evident alongside nuclear localization in neurons,
      muscle, hypodermis, and intestinal cells.
    action: ACCEPT
    reason: >-
      Direct experimental evidence confirms cytoplasmic localization of
      NHR-49. This likely reflects the dynamic shuttling of nuclear receptors
      between cytoplasm and nucleus. The dual localization is common for
      nuclear hormone receptors.
    supported_by:
    - reference_id: PMID:25474470
      supporting_text: >-
        In adults, it was visible in all somatic tissues (Fig

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21611156
  review:
    summary: >-
      PMID:21611156 (Meissner et al. 2011) is a high-throughput localizome
      study determining sub-cellular localization of proteins within C. elegans
      body wall muscle using GFP tagging. NHR-49 was localized to the nucleus
      in this study. While this is body wall muscle-specific data, it is
      consistent with the broader expression and localization data from
      PMID:25474470.
    action: ACCEPT
    reason: >-
      The HDA evidence from the muscle localizome study confirms nuclear
      localization and is consistent with the IDA evidence from PMID:25474470
      and the predicted nuclear localization from domain analysis.
    supported_by:
    - reference_id: PMID:21611156
      supporting_text: >-
        we have analyzed the expression of about 227 GFP-tagged proteins
        that show localized expression in the body wall muscle of this
        nematode

- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:15719061
  review:
    summary: >-
      PMID:15719061 (Van Gilst et al. 2005) is the seminal study
      characterizing NHR-49 function. It demonstrated that nhr-49(nr2041)
      deletion mutants have dramatically shortened lifespan (6-8 days vs.
      15-18 days for wild type at 23C), representing approximately 41%
      reduction in adult lifespan. The authors showed a striking correlation
      between fatty acid desaturase activity (stearic/oleic acid ratio) and
      lifespan, suggesting the shortened lifespan results at least in part
      from impaired fat-7 expression.
    action: ACCEPT
    reason: >-
      Determination of adult lifespan is a core phenotype of nhr-49 loss of
      function. The ~41% reduction in lifespan is one of the most dramatic
      effects reported for nhr-49 mutants and has been replicated across
      multiple studies. Falcon deep research lists shortened lifespan among
      the core loss-of-function phenotypes of nhr-49.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49(nr2041) worms lived only 6–8 d as adults, significantly
        shorter than the 15 to 18-d life span of N2 wild-type (WT) animals
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49 function is not required for development or fertility, but
        is clearly essential for normal longevity
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        Loss of **nhr-49** causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology and function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection

- term:
    id: GO:0019217
    label: regulation of fatty acid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:15719061
  review:
    summary: >-
      PMID:15719061 (Van Gilst et al. 2005) comprehensively demonstrated that
      NHR-49 regulates expression of 13 fatty acid metabolism genes, including
      six in beta-oxidation (acs-2, ech-1, F09F3.9), three delta-9 desaturases
      (fat-5, fat-7, and to a lesser extent fat-6), and genes in fatty acid
      binding/transport and the glyoxylate pathway. Loss of nhr-49 results in
      increased fat storage and altered fatty acid composition with elevated
      stearic-to-oleic acid ratio.
    action: ACCEPT
    reason: >-
      Regulation of fatty acid metabolism is the most central function of
      NHR-49. The evidence from PMID:15719061 is comprehensive, showing
      effects on both beta-oxidation and desaturation pathways, with
      measurable changes in fat storage and fatty acid composition. Falcon
      deep research confirms the central role of NHR-49 in activating
      beta-oxidation targets (acs-2, cpt-5, ech-1) and desaturase genes
      (fat-5, fat-6, fat-7).
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        Our screen revealed that deletion of nhr-49 significantly altered the
        expression of 13 genes, including six genes predicted to be involved
        in fatty acid β-oxidation, three genes involved in fatty acid
        desaturation
    - reference_id: PMID:15719061
      supporting_text: >-
        nhr-49(nr2041) animals stained more brightly with Nile Red than did
        WT worms
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        It activates gene modules involved in **fatty-acid β-oxidation** (including canonical targets such as **acs-2, cpt-5, ech-1**) and regulates **fatty-acid desaturation** genes (**fat-5, fat-6, fat-7**)

- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:15719061
  review:
    summary: >-
      PMID:15719061 (Van Gilst et al. 2005) showed that NHR-49 promotes
      transcription of target genes including acs-2, fat-5, fat-7, and ech-1.
      Expression of these genes was dramatically reduced (>30-fold for fat-5
      and fat-7) in nhr-49 deletion mutants. NHR-49 also works with Mediator
      subunit MDT-15 for transcriptional activation (PMID:16651656).
    action: ACCEPT
    reason: >-
      Positive regulation of Pol II transcription is a core molecular
      function of NHR-49 as a transcription factor that activates expression
      of fatty acid metabolism genes. The evidence is strong and direct.
    supported_by:
    - reference_id: PMID:15719061
      supporting_text: >-
        fat-5 (W06D12.3) and fat-7 (F10D2.9) expression was dramatically
        lowered in nhr-49(nr2041) worms (>30-fold) in all four larval stages
    - reference_id: PMID:16651656
      supporting_text: >-
        Knockdown of mdt-15 by RNA interference (RNAi) prevented
        fasting-induced mRNA accumulation of NHR-49 targets in vivo

- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:16839188
  review:
    summary: >-
      PMID:16839188 (Brock et al. 2006) characterized nhr-80 and delta-9
      desaturase mutants, with nhr-49 as a comparison. The study confirmed
      that nhr-49 mutants have a 41% reduction in mean lifespan (8.2 days
      vs 13.9 days at 25C) and importantly showed that nhr-80 mutants, despite
      similar fatty acid composition changes, have only a modest ~10% lifespan
      reduction. This demonstrates that the short lifespan of nhr-49 is not
      solely due to desaturase deficiency but involves additional metabolic
      functions (e.g., beta-oxidation).
    action: ACCEPT
    reason: >-
      This provides independent replication of the nhr-49 lifespan phenotype
      and adds the important insight that the lifespan effect is not solely
      attributable to desaturase regulation. Determination of adult lifespan
      is a core function of nhr-49.
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        These data indicate a 10% decrease in mean lifespan between wild type
        and nhr-80 mutants, the difference between wild type and nhr-49
        mutants is much greater with a 41% reduction in mean lifespan.

- term:
    id: GO:0019216
    label: regulation of lipid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:16839188
  review:
    summary: >-
      PMID:16839188 (Brock et al. 2006) confirmed that nhr-49 mutants have
      altered fatty acid composition similar to nhr-80 mutants (elevated
      18:0/18:1 ratio), but additionally showed increased fat storage not
      seen in nhr-80 mutants. NHR-49 regulates both desaturation (via fat-5,
      fat-7) and beta-oxidation pathways, having broader lipid regulatory
      functions than NHR-80 alone.
    action: ACCEPT
    reason: >-
      Regulation of lipid metabolism is a core function of NHR-49. While
      GO:0019217 (regulation of fatty acid metabolic process) from
      PMID:15719061 is more specific, this broader term also captures NHR-49
      roles in sphingolipid processing and lipid remodeling (PMID:22511885)
      that go beyond fatty acid metabolism. Falcon deep research describes
      NHR-49 as coordinating transcriptional programs that balance lipid
      catabolism, fatty-acid desaturation, and lipid remodeling, including
      NHR-66-dependent sphingolipid/lipid remodeling programs.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:16839188
      supporting_text: >-
        The nhr-49 mutants have increased levels of the saturated fatty acid
        18:0, higher fat accumulation, and a shorter lifespan than wild-type
        animals
    - reference_id: PMID:22511885
      supporting_text: >-
        We show that NHR-49 regulates distinct subsets of its target genes by
        partnering with at least two other distinct nuclear receptors
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        **NHR-66**: linked to regulation of **sphingolipid/lipid remodeling** genes.

- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IMP
  original_reference_id: PMID:35285794
  review:
    summary: >-
      PMID:35285794 (Doering et al. 2022) demonstrated that NHR-49 acts in
      parallel with HIF-1 to promote hypoxia adaptation. Under 0.5% oxygen,
      NHR-49 activates expression of acs-2, fmo-2, and autophagy-related genes.
      Loss of nhr-49 reduces embryonic hypoxia survival from 86% to 25%.
      Combined loss of nhr-49 and hif-1 is nearly lethal under hypoxia (<2%
      survival). NHR-49 acts in multiple somatic tissues including intestine,
      head neurons, and hypodermal seam cells.
    action: NEW
    reason: >-
      This annotation captures the well-documented role of NHR-49 in hypoxia
      adaptation, which is a distinct biological function from its lipid
      metabolism role. The evidence from Doering et al. 2022 is strong with
      clear survival phenotypes and target gene identification. Falcon deep
      research highlights this as an essential hypoxia survival pathway acting
      in parallel to HIF-1, with NHR-49 required for hypoxia-induced
      autophagosome (LGG-1::GFP) formation in seam cells.
    additional_reference_ids:
    - file:worm/nhr-49/nhr-49-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:35285794
      supporting_text: >-
        nhr-49 is not only required to induce fmo-2, but controls a broad
        transcriptional response to hypoxia
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        an **essential hypoxia survival pathway** controlled by NHR-49 that operates **in parallel to HIF-1**
    - reference_id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
      supporting_text: |-
        NHR-49 being required for hypoxia-induced autophagosome formation (LGG-1::GFP foci) in seam cells

core_functions:
- molecular_function:
    id: GO:0004879
    label: nuclear receptor activity
  description: >-
    NHR-49 acts as a nuclear receptor transcription factor to regulate fatty
    acid metabolism genes through heterodimerization with partner NHRs. The
    NHR-49/NHR-80 heterodimer activates delta-9 desaturase genes (fat-5,
    fat-7), while NHR-49/NHR-66 represses sphingolipid and lipid remodeling
    genes. NHR-49 independently promotes beta-oxidation gene expression
    (acs-2, ech-1, cpt-5). The Mediator subunit MDT-15 serves as a
    transcriptional coactivator for NHR-49 target genes.
  directly_involved_in:
  - id: GO:0019217
    label: regulation of fatty acid metabolic process
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:15719061
    supporting_text: >-
      Our screen revealed that deletion of nhr-49 significantly altered the
      expression of 13 genes, including six genes predicted to be involved in
      fatty acid beta-oxidation, three genes involved in fatty acid
      desaturation
  - reference_id: PMID:22511885
    supporting_text: >-
      We show that NHR-49 regulates distinct subsets of its target genes by partnering
      with at least two other distinct nuclear receptors
  - reference_id: PMID:16651656
    supporting_text: >-
      elegans Mediator complex, as an NHR-49-interacting protein and transcriptional
      coactivator

- molecular_function:
    id: GO:0004879
    label: nuclear receptor activity
  description: >-
    NHR-49 acts as a nuclear receptor cofactor required for longevity mediated
    by germline loss (glp-1) and LIPL-4/LBP-8 lysosomal lipid signaling.
    Upon germline removal, NHR-49 is transcriptionally upregulated by
    DAF-16/FOXO and TCER-1/TCERG1 and promotes beta-oxidation gene
    expression. In the LIPL-4/LBP-8/OEA pathway, NHR-49 acts together with
    NHR-80 (the direct OEA receptor) as a downstream effector. NHR-49 does
    not bind OEA directly. Loss of nhr-49 causes approximately 41% lifespan
    reduction and completely suppresses germline-loss longevity but is not
    required for daf-2/IIS longevity.
  directly_involved_in:
  - id: GO:0008340
    label: determination of adult lifespan
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:25474470
    supporting_text: >-
      We found that two independent RNAi clones targeting nhr-49 completely abrogated
      the longevity of glp-1 mutants (Fig
  - reference_id: PMID:25554789
    supporting_text: >-
      Nuclear hormone receptors nhr-49 and nhr-80, previously demonstrated to physically
      interact (10), were both required for lipl-4–and lbp-8–mediated longevity
  - reference_id: PMID:15719061
    supporting_text: >-
      At 23 °C, nhr-49(nr2041) worms lived only 6–8 d as adults, significantly shorter
      than the 15 to 18-d life span of N2 wild-type (WT) animals (Figure 1A)

- molecular_function:
    id: GO:0004879
    label: nuclear receptor activity
  description: >-
    NHR-49 acts as a nuclear receptor transcription factor promoting hypoxia
    adaptation in parallel with HIF-1. Under 0.5% oxygen, NHR-49 activates
    expression of acs-2, fmo-2, and autophagy-related genes. NHR-49 acts in
    multiple somatic tissues including intestine, head neurons, and
    hypodermal seam cells. Loss of nhr-49 reduces embryonic hypoxia survival
    from 86% to 25%, and combined loss with hif-1 is nearly lethal under
    hypoxia.
  directly_involved_in:
  - id: GO:0071456
    label: cellular response to hypoxia
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:35285794
    supporting_text: >-
      Here, we show that nhr-49 is not only required to induce fmo-2, but controls
      a broad transcriptional response to hypoxia, including the induction of autophagy,
      a process required within the nhr-49 pathway for survival in hypoxia

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: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: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: PMID:14704431
  title: A map of the interactome network of the metazoan C. elegans.
  findings:
  - statement: High-throughput yeast two-hybrid screen identifying NHR-49 protein
      interactions in C. elegans.
    supporting_text: >-
      more than 4000 interactions were identified from high-throughput, yeast
      two-hybrid (HT=Y2H) screens
- id: PMID:15719061
  title: Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition
    in C. elegans.
  findings:
  - statement: NHR-49 regulates fatty acid beta-oxidation genes (acs-2, ech-1) and
      desaturation genes (fat-5, fat-7), controlling fat consumption and fatty acid
      composition.
    supporting_text: >-
      Our screen revealed that deletion of nhr-49 significantly altered the
      expression of 13 genes, including six genes predicted to be involved in
      fatty acid β-oxidation, three genes involved in fatty acid desaturation
  - statement: nhr-49(nr2041) deletion causes approximately 41% lifespan reduction,
      increased fat storage, and elevated stearic-to-oleic acid ratio.
    supporting_text: >-
      nhr-49(nr2041) worms lived only 6–8 d as adults, significantly shorter than
      the 15 to 18-d life span of N2 wild-type (WT) animals
  - statement: fat-7 RNAi reproduces the shortened lifespan phenotype of nhr-49 mutants,
      suggesting the lifespan defect results at least in part from impaired desaturase
      expression.
    supporting_text: >-
      the effect of fat-7 RNAi on life span was even more potent than nhr-49
      deletion, reducing adult life span to 3–5 d
- id: PMID:16651656
  title: A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism
    by NHR-49-dependent and -independent pathways in C. elegans.
  findings:
  - statement: MDT-15 identified as NHR-49 physical interacting partner and transcriptional
      coactivator for fatty acid metabolism gene regulation.
    supporting_text: >-
      we report the identification of MDT-15, a subunit of the C. elegans Mediator
      complex, as an NHR-49-interacting protein and transcriptional coactivator
  - statement: MDT-15 also regulates fat-6 independently of NHR-49, indicating additional
      regulatory factors recruit MDT-15.
    supporting_text: >-
      mdt-15 RNAi affected additional FA-metabolism genes (including the third
      FA-Δ9-desaturase, fat-6) that are regulated independently of NHR-49
- id: PMID:16839188
  title: Genetic regulation of unsaturated fatty acid composition in C. elegans.
  findings:
  - statement: NHR-80 identified as a novel regulator of delta-9 desaturase expression
      with phenotypes similar to but distinct from nhr-49 mutants.
    supporting_text: >-
      We found an RNAi clone, nhr-80, that caused C. elegans to accumulate
      increased levels of 18:0
  - statement: nhr-49 mutants have 41% lifespan reduction compared to only 10% for
      nhr-80 mutants despite similar fatty acid composition changes.
    supporting_text: >-
      These data indicate a 10% decrease in mean lifespan between wild type and
      nhr-80 mutants, the difference between wild type and nhr-49 mutants is much
      greater with a 41% reduction in mean lifespan
  - statement: NHR-80 is required for compensatory upregulation of fat-7 in fat-6
      mutants; fat-6;nhr-80 double mutants are synthetically lethal.
    supporting_text: >-
      NHR-80 is required for increasing fat-7 expression in situations where higher
      fat-7 levels are necessary
- id: PMID:19123269
  title: Empirically controlled mapping of the Caenorhabditis elegans protein-protein
    interactome network.
  findings:
  - statement: Expanded C. elegans interactome map from systematic Y2H screening including
      NHR-49 interactions.
    supporting_text: >-
      we present an expanded C. elegans protein-protein interaction network
- id: PMID:21611156
  title: Determining the sub-cellular localization of proteins within Caenorhabditis
    elegans body wall muscle.
  findings:
  - statement: High-throughput GFP-tagging localizome study showing NHR-49 nuclear
      localization in body wall muscle cells.
    supporting_text: >-
      we have analyzed the expression of about 227 GFP-tagged proteins that show
      localized expression in the body wall muscle of this nematode
- id: PMID:22511885
  title: Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships.
  findings:
  - statement: NHR-49 forms heterodimers with NHR-80 (desaturation pathway), NHR-66
      (sphingolipid pathway), and NHR-13 (desaturation pathway).
    supporting_text: >-
      We show that NHR-49 regulates distinct subsets of its target genes by
      partnering with at least two other distinct nuclear receptors
  - statement: NHR-49 also homodimerizes and may interact with NHR-22, NHR-79, NHR-105,
      and NHR-256.
    supporting_text: >-
      Gene expression profiles suggest that NHR-49 partners with NHR-66 to
      regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate
      genes involved in fatty acid desaturation
  - statement: nhr-49 mutants have altered mitochondrial morphology, and sphingolipid
      and lipid remodeling genes are newly identified NHR-49 targets.
    supporting_text: >-
      nhr-49 animals had significantly altered mitochondrial morphology
- id: PMID:23791784
  title: Extensive rewiring and complex evolutionary dynamics in a C. elegans multiparameter
    transcription factor network.
  findings:
  - statement: Systematic characterization of TF network rewiring showing NHR-49 interactions
      across multiple molecular networks in C. elegans.
    supporting_text: >-
      we comprehensively characterize such network rewiring for C. elegans
      transcription factors (TFs) within and across four newly delineated molecular
      networks
- id: PMID:24107417
  title: TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants.
  findings:
  - statement: NHR-49 identified among transcription factors with roles in development,
      stress response, and fecundity of isp-1 Mit mutants.
    supporting_text: >-
      Seven of these transcription factors--AHA-1, CEH-18, HIF-1, JUN-1, NHR-27,
      NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein TAF-4--were also
      essential for isp-1 life extension.
- id: PMID:24854345
  title: PKG and NHR-49 signalling co-ordinately regulate short-term fasting-induced
    lysosomal lipid accumulation in C. elegans.
  findings:
  - statement: NHR-49 acts in intestine during short-term fasting to regulate lysosomal
      lipid accumulation via activation of IPLA-2 and lysosomal hydrolases.
    supporting_text: >-
      NHR-49 acts in intestine to inhibit lipids accumulation via activation of
      IPLA-2
  - statement: EGL-4/PKG acts in sensory neurons while NHR-49 acts in intestine, coordinating
      the fasting-induced lysosomal response.
    supporting_text: >-
      EGL-4 acts in sensory neurons to enhance lysosomal lipid accumulation
      through inhibiting the DAF-3/SMAD pathway, whereas NHR-49 acts in intestine
- id: PMID:25474470
  title: Germline signals deploy NHR-49 to modulate fatty-acid β-oxidation and desaturation
    in somatic tissues of C. elegans.
  findings:
  - statement: NHR-49 is essential for germline-loss-mediated longevity in glp-1 mutants
      but dispensable for daf-2/IIS longevity.
    supporting_text: >-
      nhr-49 has variable degrees of relevance for different physiological
      alterations that influence aging. It is critical for the longevity mediated
      by reproductive signals but is not central to the lifespan changes resulting
      from reduced IIS
  - statement: NHR-49 is transcriptionally upregulated by DAF-16 and TCER-1 in soma
      upon germline removal.
    supporting_text: >-
      NHR-49 is transcriptionally up-regulated by DAF-16 and TCER-1 in the soma
      upon germline removal
  - statement: NHR-49::GFP localizes to nuclei and cytoplasm in all somatic tissues,
      with highest expression in intestinal cells.
    supporting_text: >-
      In adults, it was visible in all somatic tissues (Fig
  - statement: NHR-49 controls expression of 7 mitochondrial beta-oxidation genes
      in germline-less animals and overexpression modestly extends fertile animal
      lifespan by approximately 15%.
    supporting_text: >-
      NHR-49 causes the increased expression of multiple genes involved in
      fatty-acid β-oxidation and desaturation
- id: PMID:25554789
  title: "Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans."
  findings:
  - statement: NHR-49 and NHR-80 are both required for LIPL-4 and LBP-8 mediated longevity
      signaling.
    supporting_text: >-
      Nuclear hormone receptors nhr-49 and nhr-80, previously demonstrated to
      physically interact (10), were both required for lipl-4–and lbp-8–mediated
      longevity
  - statement: NHR-49 does NOT bind OEA directly; NHR-80 is the direct nuclear receptor
      for OEA with Kd of approximately 7.8 uM.
    supporting_text: >-
      no binding was detected between NHR-49 and OEA or OEA analogue
  - statement: acs-2 transcription increased more than 15-fold in lipl-4 Tg animals,
      dependent on both nhr-49 and nhr-80.
    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
- id: PMID:35140229
  title: Histone H3K4me3 modification is a transgenerational epigenetic signal for
    lipid metabolism in Caenorhabditis elegans.
  findings:
  - statement: NHR-49 is required for transgenerational inheritance of lipid accumulation
      from high-fat diet, functioning as an executor but not a transmitter of heritable
      lipid memory.
    supporting_text: >-
      nhr-49 and nhr-80 functioned solely as executors
  - statement: nhr-49 mutation abrogates F1 and F2 lipid accumulation from parental
      HFD but does not affect P0 response to HFD.
    supporting_text: >-
      lipid accumulation was abrogated in F1 or F2 descendants of these mutants
  - statement: NHR-49, NHR-80, SBP-1, and DAF-16 function in parallel pathways for
      transgenerational epigenetic inheritance of lipid accumulation.
    supporting_text: >-
      daf-16, sbp-1, nhr-49 and nhr-80 function in parallel pathway during the
      stress of lipid accumulation in F1 generation
- id: PMID:35285794
  title: Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 to promote hypoxia
    adaptation in Caenorhabditis elegans.
  findings:
  - statement: NHR-49 promotes hypoxia adaptation in parallel with HIF-1, activating
      acs-2, autophagy genes, and fmo-2 during hypoxia.
    supporting_text: >-
      nhr-49 is not only required to induce fmo-2, but controls a broad
      transcriptional response to hypoxia
  - statement: nhr-49 loss reduces hypoxia survival from 86% to 25% for embryos developing
      to L4 stage.
    supporting_text: >-
      only 25% of nhr-49 and hif-1 null mutant animals reached at least the L4
      stage by that time
  - statement: NHR-49 is expressed in head, intestine, and hypodermal seam cells.
    supporting_text: >-
      Expression is seen in the head, intestine, and hypodermal seam cells
- id: file:worm/nhr-49/nhr-49-deep-research-falcon.md
  title: Falcon deep research report on nhr-49 (C. elegans)
  findings:
  - statement: |-
      NHR-49 is a sequence-specific transcription factor of the nuclear receptor
      superfamily, functionally comparable to mammalian lipid-sensing nuclear
      receptors (PPARalpha by functional analogy, HNF4alpha by structural
      similarity), and is among the best-characterized C. elegans NHRs.
    reference_section_type: OTHER
    supporting_text: |-
      **NHR-49 is a sequence-specific transcription factor of the nuclear receptor superfamily**. It is widely described as functionally comparable to mammalian lipid-sensing nuclear receptors, especially **PPARα** (functional analogy) and **HNF4α** (structural similarity), and is among the best-characterized *C. elegans* NHRs
  - statement: |-
      The central mechanistic theme is that NHR-49 coordinates transcriptional
      programs balancing lipid catabolism (beta-oxidation), fatty-acid
      desaturation, lipid remodeling, and stress-protective responses.
    reference_section_type: OTHER
    supporting_text: |-
      the central mechanistic theme is that **NHR-49 coordinates transcriptional programs that balance lipid catabolism (β-oxidation), fatty-acid desaturation, lipid remodeling, and stress-protective responses**
  - statement: |-
      NHR-49 acts as a transcriptional regulator that can both activate and
      repress metabolic gene programs, activating fatty-acid beta-oxidation
      targets (acs-2, cpt-5, ech-1) and regulating desaturases (fat-5, fat-6,
      fat-7).
    reference_section_type: OTHER
    supporting_text: |-
      **Primary function**: NHR-49 acts as a **transcriptional regulator** that can both **activate** and **repress** metabolic gene programs.
      - It activates gene modules involved in **fatty-acid β-oxidation** (including canonical targets such as **acs-2, cpt-5, ech-1**) and regulates **fatty-acid desaturation** genes (**fat-5, fat-6, fat-7**)
  - statement: |-
      NHR-49 regulates distinct gene subsets via context-dependent partnerships
      with other NHRs: NHR-80 for fatty-acid desaturase genes and NHR-66 for
      sphingolipid/lipid remodeling genes.
    reference_section_type: OTHER
    supporting_text: |-
      NHR-49 was shown to regulate distinct gene subsets via **partnerships with other NHRs**, notably:
      - **NHR-80**: linked to regulation of **fatty-acid desaturase** genes.
      - **NHR-66**: linked to regulation of **sphingolipid/lipid remodeling** genes.
  - statement: |-
      MDT-15 (a Mediator subunit) is a critical co-regulator for NHR-49-driven
      transcriptional outputs in metabolism and stress programs.
    reference_section_type: OTHER
    supporting_text: |-
      Multiple studies converge on **MDT-15 (Mediator subunit)** as a critical co-regulator for NHR-49-driven transcriptional outputs in metabolism and stress programs
  - statement: |-
      NHR-49 is an orphan nuclear receptor: its ligand-binding domain is
      functionally important and likely ligand-responsive, but no definitive
      endogenous ligand has been established, so any ligand should be phrased as
      putative.
    reference_section_type: OTHER
    supporting_text: |-
      Evidence strongly supports that **the LBD is functionally important** and likely ligand-responsive, but **a definitive endogenous ligand for NHR-49 is not established**.
  - statement: |-
      NHR-49 controls an essential hypoxia survival pathway that operates in
      parallel to HIF-1, being required for hypoxia-induced autophagosome
      (LGG-1::GFP) formation in seam cells.
    reference_section_type: OTHER
    supporting_text: |-
      A major mechanistic expansion beyond “lipid metabolism” is an **essential hypoxia survival pathway** controlled by NHR-49 that operates **in parallel to HIF-1**, with NHR-49 being required for hypoxia-induced autophagosome formation (LGG-1::GFP foci) in seam cells
  - statement: |-
      NHR-49/MDT-15 couples lipid metabolic remodeling to HSF-1-dependent heat
      shock response and proteostasis; intestinal NHR-49 activation improves
      proteostasis outcomes (Sala et al. 2024, Genes & Development).
    reference_section_type: OTHER
    supporting_text: |-
      A 2024 Genes & Development study places NHR-49/MDT-15 as a signaling module that links lipid metabolic remodeling to **HSF-1-dependent heat shock response** and proteostasis
  - statement: |-
      A cell-autonomous neuronal role for NHR-49 in oxygen-sensing URX/AQR/PQR
      neurons is required for pathogen (PA14) lawn avoidance and normal neuronal
      calcium kinetics (Kwon et al. 2024, Cells).
    reference_section_type: OTHER
    supporting_text: |-
      A 2024 Cells paper identifies a **cell-autonomous neuronal role**: loss of nhr-49 causes impaired pathogen lawn avoidance (PA14) associated with **prolonged URX calcium transients after O2 upshift**, and neuronal rescue in URX/AQR/PQR improves both behavior and calcium kinetics
  - statement: |-
      Loss of nhr-49 causes high fat, impaired fasting response, shortened
      lifespan, altered mitochondrial morphology/function, defective pathogen
      avoidance, and increased sensitivity to oxidative stress, hypoxia, and
      infection.
    reference_section_type: OTHER
    supporting_text: |-
      Loss of **nhr-49** causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology and function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection
  - statement: |-
      NHR-49 is required for induction of phase II detoxification programs in
      oxidative stress contexts and works with MDT-15.
    reference_section_type: OTHER
    supporting_text: |-
      NHR-49 is required for induction of detoxification programs (phase II enzymes) in oxidative stress contexts and works with MDT-15