Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: LBP-8 nuclear localization is well-established by direct experimental evidence (PMID:25554789). Folick et al. demonstrated partial nuclear localization of LBP-8 in the intestine, enhanced upon LIPL-4 overexpression. LBP-8 was detected in nuclear fractions of total worm lysate. The IBA annotation is consistent with all available evidence. Reason: Nuclear localization is a core feature of LBP-8 function, demonstrated by fluorescent tagging and subcellular fractionation (PMID:25554789). Tillman et al. (PMID:31292465) further identified a structurally conserved NLS (K24, R33, K34) required for nuclear translocation. The IBA annotation is phylogenetically sound and experimentally validated. Supporting Evidence: PMID:25554789 We also detected partial nuclear localization of LBP-8 in the intestine, which was enhanced in lipl-4 Tg animals PMID:31292465 we determined the first 1.3 Å high-resolution structure of this life-extending protein LBP-8, which allowed us to identify a structurally conserved nuclear localization signal file:worm/lbp-8/lbp-8-deep-research-falcon.md conserved, structural nuclear localization signal (NLS) formed by basic residues (K24/R33/K34). Deletion/mutation of this region abolishes nuclear translocation.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: LBP-8 is an intracellular lipid-binding protein and, as a soluble FABP, would be expected to be present in the cytosol. Folick et al. (PMID:25554789) detected LBP-8 in cytoplasmic fractions. The IBA annotation is phylogenetically reasonable for FABPs. Reason: Cytosolic localization is expected for a soluble FABP family member. LBP-8 was detected in cytoplasmic fractions (PMID:25554789), and as a lipid shuttle between lysosomes and nucleus, it transits through the cytosol. The IBA annotation is consistent with evidence. Supporting Evidence: PMID:25554789 LBP-8 contains an N-terminal nuclear localization signal (NLS) ... and was present in both cytoplasmic and nuclear fractions of total worm lysate file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 is predominantly lysosomal in intestinal cells, co-localizing with lysosomal marker LMP-1, and also appears in nuclear and cytosolic fractions
GO:0005504 fatty acid binding	IBA GO_REF:0000033	ACCEPT	Summary: LBP-8 fatty acid binding is well-established experimentally. Folick et al. (PMID:25554789) showed LBP-8 binds arachidonic acid, omega-3 arachidonic acid, DGLA, and OEA. Tillman et al. (PMID:31292465) used mass spectrometry to identify a broad range of fatty acids co-purifying with LBP-8, with preference for monounsaturated fatty acids. The IBA annotation is appropriate and at the right level of specificity for the FABP family. Reason: Fatty acid binding is the central molecular function of LBP-8 as a FABP family member. Extensive experimental validation by both fluorescence-based binding assays (PMID:25554789) and LC/MS (PMID:31292465). The IBA annotation is at an appropriate level. Supporting Evidence: PMID:31292465 we described the range of fatty acids LBP-8 is capable of binding and show that it binds to life-extending ligands in worms such as oleic acid and oleoylethanolamide with high affinity PMID:25554789 all four lipids bound to LBP-8, and the binding affinity of OEA for LBP-8 was 3 times higher than that of the fatty acids file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 binds long-chain fatty acids and fatty-acid derivatives. file:worm/lbp-8/lbp-8-deep-research-falcon.md Reported ligands include oleoylethanolamide (OEA), oleic acid, arachidonic acid (AA), ω-3 AA, and DGLA; competition assays showed OEA binds with ~3-fold higher affinity than the tested fatty acids.
GO:0015908 fatty acid transport	IBA GO_REF:0000033	ACCEPT	Summary: LBP-8 functions as an intracellular fatty acid transporter, shuttling lipid signals from lysosomes to the nucleus (PMID:25554789). The IBA annotation for fatty acid transport is phylogenetically sound and at the right level of specificity. Reason: LBP-8 is an intracellular lipid chaperone that transports fatty acids and their derivatives from lysosomes to the nucleus (PMID:25554789). This is its core biological process. The IBA annotation at the level of fatty acid transport is appropriate. Supporting Evidence: PMID:25554789 LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals to the nucleus PMID:31292465 supporting the role of LBP-8 as a shuttling protein for monounsaturated fatty acids and their derivatives file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 carries lipid ligands (notably OEA) to nuclear hormone receptor machinery
GO:0005504 fatty acid binding	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for fatty acid binding via ARBA machine learning. This is consistent with the experimentally validated function of LBP-8 as a FABP. Duplicates the IBA annotation but is acceptable as an independent computational prediction. Reason: The IEA annotation is correct and consistent with extensive experimental evidence for fatty acid binding by LBP-8 (PMID:25554789, PMID:31292465). It is a valid independent computational prediction that agrees with the IBA annotation.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for nuclear localization based on UniProt subcellular location mapping. Consistent with IDA evidence from PMID:25554789 showing LBP-8 in the nucleus. Reason: The IEA annotation correctly reflects the experimentally determined nuclear localization of LBP-8 (PMID:25554789). UniProt mapping is appropriate here.
GO:0005764 lysosome	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for lysosomal localization based on UniProt subcellular location mapping. Consistent with IDA evidence from PMID:25554789 showing LBP-8 localization to lysosomes. Reason: The IEA annotation correctly reflects the experimentally determined lysosomal localization of LBP-8. Folick et al. (PMID:25554789) showed FLAG- and mCherry-tagged LBP-8 predominantly localized to intestinal lysosomes. Supporting Evidence: PMID:25554789 Both FLAG- and mCherry-tagged LBP-8 proteins were predominantly localized to intestinal lysosomes file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 is predominantly lysosomal in intestinal cells, co-localizing with lysosomal marker LMP-1
GO:0008289 lipid binding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for lipid binding based on InterPro domain mapping. LBP-8 contains the FABP domain (IPR000463). This is a broader parent term of fatty acid binding (GO:0005504), which is already annotated with more specific evidence. The IEA is acceptable as it captures the InterPro-based prediction, though it is less specific than the IBA/IDA annotations. Reason: The IEA annotation is correct but broader than the more specific fatty acid binding annotations already present. It is acceptable as an independent InterPro-based prediction. LBP-8 binds diverse lipids including fatty acids and OEA (PMID:25554789, PMID:31292465). Supporting Evidence: file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 binds long-chain fatty acids and fatty-acid derivatives.
GO:0070538 oleic acid binding	IDA PMID:31292465 Structural characterization of life-extending Caenorhabditis...	ACCEPT	Summary: Tillman et al. (PMID:31292465) directly demonstrated oleic acid binding to LBP-8 using competitive fluorescence-based binding assays and mass spectrometry. Oleic acid was the most abundant fatty acid co-purifying with LBP-8 from both E. coli and C. elegans lipid extracts. Oleic acid and OEA had similar high-affinity Ki values. This is a well-supported IDA annotation. Reason: Oleic acid binding is directly demonstrated by competitive fluorescence binding assays and LC/MS co-purification in PMID:31292465. Oleic acid was the most abundant fatty acid bound to LBP-8 (28.93% from C. elegans extracts, 35.72% from E. coli). This specific binding activity is core to LBP-8 function. Supporting Evidence: PMID:31292465 A fluorescence-based ligand binding assay was used to compare the affinity of oleic acid and OEA, and both had very similar Ki's, suggesting oleic acid, along with OEA, are high affinity ligands of LBP-8 PMID:31292465 While the relative percentage of oleic acid decreased, it was still the most abundant fatty acid that bound to LBP-8 file:worm/lbp-8/lbp-8-deep-research-falcon.md identifies co-purifying palmitic (16:0) and oleic (18:1) acids from E. coli and, after exposure to worm extracts, enrichment for myristic (14:0) and unsaturated fatty acids including arachidonic (20:4), linoleic (18:2), and palmitoleic (16:1); oleic acid remained most abundant.
GO:0005324 long-chain fatty acid transmembrane transporter activity	IMP PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C...	MODIFY	Summary: GO:0005324 (long-chain fatty acid transporter activity) is defined as enabling transfer of long-chain fatty acids from one side of a membrane to the other. LBP-8 is not a transmembrane transporter. It is a soluble intracellular lipid chaperone that shuttles fatty acids between cellular compartments (lysosomes to nucleus) through the cytosol. Folick et al. (PMID:25554789) showed LBP-8 translocates from lysosomes to the nucleus carrying lipid signals, but this is intracellular lipid transfer, not transmembrane transport. The IMP evidence is based on lbp-8 mutant phenotypes affecting lipid signaling, not transmembrane transport assays. Reason: The term GO:0005324 (long-chain fatty acid transporter activity) specifically describes transmembrane transport activity, which is not the mechanism by which LBP-8 functions. LBP-8 is a soluble lipid chaperone that binds fatty acids and shuttles them intracellularly (PMID:25554789, PMID:31292465). A more appropriate MF term would be lipid transfer activity (GO:0120013), defined as removing a lipid from a membrane, transporting it through the aqueous phase in a hydrophobic pocket, and delivering it to an acceptor. This matches the LBP-8 mechanism precisely. Proposed replacements: lipid transfer activity Supporting Evidence: PMID:25554789 LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals to the nucleus PMID:31292465 certain human FABPs have been shown to shuttle nuclear receptor ligands into the nucleus to regulate nuclear receptor transcription file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 is a non-enzymatic intracellular lipid chaperone that transfers lysosome-derived lipid signals to the nucleus. It does not catalyze a reaction; instead, it binds hydrophobic ligands and facilitates their delivery to transcriptional regulators.
GO:0005634 nucleus	IDA PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C...	ACCEPT	Summary: Folick et al. (PMID:25554789) directly showed nuclear localization of LBP-8 in the intestine using fluorescent tagging (mCherry, FLAG) and subcellular fractionation. Nuclear localization was enhanced in LIPL-4 overexpressing animals. LBP-8 was present in nuclear fractions. Deletion of the NLS abolished nuclear localization and lifespan extension. Reason: Nuclear localization is a core feature of LBP-8 function, directly demonstrated by IDA evidence in PMID:25554789. LBP-8 translocates to the nucleus to deliver lipid signals to nuclear hormone receptors NHR-49 and NHR-80. Supporting Evidence: PMID:25554789 We also detected partial nuclear localization of LBP-8 in the intestine, which was enhanced in lipl-4 Tg animals PMID:25554789 LBP-8 contains an N-terminal nuclear localization signal (NLS) ... and was present in both cytoplasmic and nuclear fractions of total worm lysate file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 is experimentally characterized as a lipid chaperone that translocates between lysosome and nucleus and drives transcriptional outputs via nuclear receptors.
GO:0005764 lysosome	IDA PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C...	ACCEPT	Summary: Folick et al. (PMID:25554789) directly showed LBP-8 localization to intestinal lysosomes using FLAG and mCherry tagging with colocalization studies. LBP-8 was predominantly found at lysosomes under basal conditions, with nuclear translocation enhanced upon LIPL-4 overexpression. Reason: Lysosomal localization is a core feature of LBP-8, demonstrated by direct fluorescent microscopy and colocalization in PMID:25554789. This localization is central to LBP-8's role in the lysosome-to-nucleus signaling pathway. Supporting Evidence: PMID:25554789 Both FLAG- and mCherry-tagged LBP-8 proteins were predominantly localized to intestinal lysosomes file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 is predominantly lysosomal in intestinal cells, co-localizing with lysosomal marker LMP-1, and also appears in nuclear and cytosolic fractions; lipl-4 overexpression enhances the nuclear fraction.
GO:0015909 long-chain fatty acid transport	IMP PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C...	ACCEPT	Summary: Folick et al. (PMID:25554789) demonstrated that LBP-8 is required for LIPL-4-mediated longevity signaling, which involves transport of lipid signals (including long-chain fatty acids and OEA) from lysosomes to the nucleus. The IMP evidence comes from lbp-8 loss-of-function suppressing lipl-4-mediated lifespan extension. While the biological process annotation is broadly correct, the transport is intracellular rather than across membranes. Reason: Long-chain fatty acid transport is an appropriate biological process term for LBP-8. The GO:0015909 definition includes movement "within a cell", which accurately describes LBP-8's intracellular lipid shuttling function. The IMP evidence is sound: lbp-8 mutants suppress lipl-4-mediated longevity and lipid signaling (PMID:25554789). Supporting Evidence: PMID:25554789 Both RNA interference (RNAi)-mediated depletion of LBP-8 and a newly isolated deletion mutant, lbp-8(rax1), suppressed the lifespan extension in lipl-4 Tg animals PMID:31292465 supporting the role of LBP-8 as a shuttling protein for monounsaturated fatty acids and their derivatives file:worm/lbp-8/lbp-8-deep-research-falcon.md functions as a lysosome-to-nucleus lipid chaperone
GO:0036041 long-chain fatty acid binding	IDA PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C...	ACCEPT	Summary: Folick et al. (PMID:25554789) demonstrated LBP-8 binding to long-chain fatty acids (arachidonic acid, omega-3 arachidonic acid, DGLA) and OEA using fluorescence-based binding assays. Tillman et al. (PMID:31292465) confirmed and extended this with LC/MS showing binding to a diverse range of long-chain fatty acids including oleic acid, arachidonic acid, linoleic acid, palmitic acid, and stearic acid. Reason: Long-chain fatty acid binding is directly demonstrated by IDA evidence. Fluorescence-based binding assays (PMID:25554789) and mass spectrometry co-purification (PMID:31292465) both confirm LBP-8 binds diverse long-chain fatty acids. This is a core molecular function and the term is at the right level of specificity. Supporting Evidence: PMID:25554789 we focused our analysis on three C20 fatty acids—arachidonic acid (AA), ω-3 arachidonic acid (ω-3 AA), and dihomo-γ-linolenic acid (DGLA)—and oleoylethanolamide (OEA) ... all four lipids bound to LBP-8 PMID:31292465 LBP-8 does not bind to one fatty acid selectively but is capable of binding many fatty acids. However, LBP-8 does have a preference for unsaturated fatty acids file:worm/lbp-8/lbp-8-deep-research-falcon.md a preference for monounsaturated fatty acyls
GO:0006869 lipid transport	TAS PMID:10693745 Secretion of a novel class of iFABPs in nematodes: coordinat...	ACCEPT	Summary: Plenefisch et al. (PMID:10693745) identified LBP-8 as one of nine C. elegans FABP homologs. The paper primarily focused on LBP-1, LBP-2, and LBP-3 (the secreted FABPs), and did not directly study LBP-8 function. The TAS evidence for lipid transport is based on homology to other FABPs. While the annotation is correct (LBP-8 does transport lipids), the evidence is weak for this specific gene. However, the annotation itself is valid given later experimental confirmation. Reason: Lipid transport is a correct annotation for LBP-8, now thoroughly validated by later experimental work (PMID:25554789, PMID:31292465). While the original TAS reference (PMID:10693745) mainly studied other C. elegans FABPs (LBP-1, LBP-2, LBP-3), the general assignment of lipid transport to the FABP family was appropriate. More specific annotations (long-chain fatty acid transport) are also present with stronger evidence. Supporting Evidence: PMID:10693745 at least eight potential homologues of As-p18 have been identified in the Caenorhabditis elegans genome PMID:25554789 LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals to the nucleus file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8’s primary molecular function is expected to be ligand binding and intracellular transport/targeting of hydrophobic metabolites
GO:0008289 lipid binding	TAS PMID:10693745 Secretion of a novel class of iFABPs in nematodes: coordinat...	ACCEPT	Summary: Plenefisch et al. (PMID:10693745) identified LBP-8 as a FABP homolog in C. elegans. The TAS annotation for lipid binding is based on homology to fatty acid binding proteins. While the original paper mainly studied LBP-1/2/3, the annotation is correct and validated by later work. More specific annotations (fatty acid binding, long-chain fatty acid binding, oleic acid binding) are also present. Reason: Lipid binding is correct for LBP-8, validated by extensive experimental evidence (PMID:25554789, PMID:31292465). The TAS evidence from PMID:10693745 was based on homology to known FABPs, which proved accurate. The annotation is broader than the more specific IDA/IBA annotations but acceptable. Supporting Evidence: file:worm/lbp-8/lbp-8-deep-research-falcon.md LBP-8 binds long-chain fatty acids and fatty-acid derivatives.
GO:0032365 intracellular lipid transport	IDA PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C...	NEW	Summary: LBP-8 is an intracellular lipid chaperone that shuttles fatty acid signals from lysosomes to the nucleus. Folick et al. (PMID:25554789) demonstrated lysosome-to-nucleus translocation of LBP-8 carrying lipid signals including OEA. This intracellular lipid transport function is the core biological process of LBP-8. Reason: GO:0032365 (intracellular lipid transport) is more precise than GO:0006869 (lipid transport) for describing LBP-8 function, as it specifically captures the intracellular nature of the lipid shuttling. LBP-8 transports lipids from lysosomes to nucleus within the cell. This term is not present in the current annotation set but is well-supported by experimental evidence. Supporting Evidence: PMID:25554789 LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals to the nucleus PMID:31292465 certain human FABPs have been shown to shuttle nuclear receptor ligands into the nucleus to regulate nuclear receptor transcription file:worm/lbp-8/lbp-8-deep-research-falcon.md functions as a lysosome-to-nucleus lipid chaperone

Core Functions

LBP-8 binds long-chain fatty acids and oleoylethanolamide (OEA) with high affinity and transfers them between intracellular membranes and acceptor proteins. Oleic acid and OEA are the preferred ligands. The conserved R132 residue coordinates fatty acid head groups in the binding cavity.

Molecular Function:

lipid transfer activity

Directly Involved In:

intracellular lipid transport long-chain fatty acid transport

Cellular Locations:

lysosome cytosol

Substrates:

oleic acid oleoylethanolamide

Supporting Evidence:

PMID:31292465
we described the range of fatty acids LBP-8 is capable of binding and show that it binds to life-extending ligands in worms such as oleic acid and oleoylethanolamide with high affinity
PMID:25554789
all four lipids bound to LBP-8, and the binding affinity of OEA for LBP-8 was 3 times higher than that of the fatty acids

LBP-8 shuttles OEA and oleic acid from lysosomes to the nucleus via its structurally conserved NLS (K24, R33, K34), delivering these lipid ligands to the nuclear hormone receptors NHR-49 and NHR-80. This activates transcription of beta-oxidation genes (acs-2) and promotes longevity. Nuclear translocation is enhanced by LIPL-4-generated lysosomal lipid signals and is required for lifespan extension.

Molecular Function:

lipid transfer activity

Directly Involved In:

intracellular lipid transport determination of adult lifespan

Cellular Locations:

nucleus

Supporting Evidence:

PMID:25554789
the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80
PMID:31292465
certain human FABPs have been shown to shuttle nuclear receptor ligands into the nucleus to regulate nuclear receptor transcription
PMID:30713071
Lysosomal Signaling Promotes Longevity by Adjusting Mitochondrial Activity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

LBP-8 contains the FABP domain (IPR000463), which maps to lipid binding (GO:0008289)

GO_REF:0000033

Annotation inferences using phylogenetic trees

Phylogenetic inference supports LBP-8 annotations for nucleus, cytosol, fatty acid binding, and fatty acid transport, consistent with the broader FABP family

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

UniProt subcellular location mapping correctly assigns LBP-8 to nucleus and lysosome, consistent with direct experimental evidence from PMID:25554789

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

ARBA correctly predicts fatty acid binding for LBP-8 based on sequence features

PMID:10693745

Secretion of a novel class of iFABPs in nematodes: coordinate use of the Ascaris/Caenorhabditis model systems.

LBP-8 identified as one of at least eight C. elegans homologs of the Ascaris fatty acid binding protein As-p18. The paper focused on the secreted FABPs (LBP-1, LBP-2, LBP-3) but established the FABP family membership of LBP-8.

"at least eight potential homologues of As-p18 have been identified in the Caenorhabditis elegans genome"

PMID:25554789

Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans.

LBP-8 is a lysosomal lipid chaperone that translocates from lysosomes to the nucleus upon LIPL-4 overexpression. LBP-8 overexpression extends lifespan by 30%. LBP-8 is required for LIPL-4-mediated longevity. LBP-8 binds OEA with 3-fold higher affinity than C20 fatty acids. LBP-8 nuclear localization requires its NLS. LBP-8 activates NHR-49/NHR-80-dependent transcription of acs-2. LBP-8 is exclusively expressed in the intestine.

"In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80"

PMID:31292465

Structural characterization of life-extending Caenorhabditis elegans Lipid Binding Protein 8.

Crystal structure of LBP-8 solved at 1.3 angstrom resolution (PDB 6C1Z). LBP-8 is a monomer with a typical lipocalin fold. A structurally conserved NLS (K24, R33, K34) was identified in the portal region. Mass spectrometry identified a broad range of fatty acids co-purifying with LBP-8, with preference for monounsaturated fatty acids. Oleic acid was the most abundant bound fatty acid. Both oleic acid and OEA bind with high affinity (similar Ki values). Oleic acid destabilizes LBP-8, decreasing Tm by approximately 4 degrees C, while OEA has no effect on stability.

"we determined the first 1.3 Å high-resolution structure of this life-extending protein LBP-8, which allowed us to identify a structurally conserved nuclear localization signal and amino acids involved in lipid binding"

PMID:30713071

Lysosomal Signaling Promotes Longevity by Adjusting Mitochondrial Activity.

Ramachandran et al. showed that the LIPL-4/LBP-8 lysosomal signaling pathway promotes longevity by adjusting mitochondrial activity, specifically through activation of mitochondrial beta-oxidation. This extends the understanding of LBP-8's downstream effects beyond nuclear receptor activation.

file:worm/lbp-8/lbp-8-deep-research-falcon.md

Falcon (Edison Scientific) deep research report on C. elegans lbp-8 (O02324)

LBP-8 is best annotated as a non-enzymatic intracellular lipid chaperone (FABP/iLBP, calycin/lipocalin-like fold) that binds hydrophobic ligands and delivers lysosome-derived lipid signals to nuclear transcriptional regulators rather than catalyzing a reaction.

"LBP-8 is a **non-enzymatic intracellular lipid chaperone** that transfers lysosome-derived lipid signals to the nucleus. It does **not catalyze a reaction**; instead, it binds hydrophobic ligands and facilitates their delivery to transcriptional regulators."
LBP-8 binds long-chain fatty acids and fatty-acid derivatives, including OEA, oleic acid, arachidonic acid, omega-3 AA, and DGLA, with OEA binding ~3-fold more tightly than the tested fatty acids and an overall preference for monounsaturated fatty acyls.

"Reported ligands include **oleoylethanolamide (OEA)**, **oleic acid**, **arachidonic acid (AA)**, **ω-3 AA**, and **DGLA**; competition assays showed **OEA binds with ~3-fold higher affinity** than the tested fatty acids."
LBP-8 localizes predominantly to intestinal lysosomes (co-localizing with the lysosomal marker LMP-1) and also appears in nuclear and cytosolic fractions, with lipl-4 overexpression enhancing the nuclear fraction; lbp-8 expression is reported as exclusive to the intestine.

"LBP-8 is predominantly **lysosomal in intestinal cells**, co-localizing with lysosomal marker **LMP-1**, and also appears in nuclear and cytosolic fractions; **lipl-4** overexpression enhances the nuclear fraction."
A conserved structural nuclear localization signal formed by basic residues K24/R33/K34 is required for nuclear translocation; deletion or mutation of this region abolishes nuclear import.

"conserved, structural **nuclear localization signal (NLS)** formed by basic residues (K24/R33/K34). Deletion/mutation of this region abolishes nuclear translocation."
In the lysosome-to-nucleus lipid signaling pathway LBP-8 carries OEA to nuclear hormone receptors; NHR-80 binds OEA directly (Kd = 7.841 uM) whereas no OEA binding was detected for NHR-49, consistent with NHR-49 acting as a partner rather than the direct OEA-binding receptor.

"NHR-80 binds OEA directly with **Kd = 7.841 µM** (intrinsic fluorescence assay), whereas no OEA binding was detected for NHR-49 in that study, consistent with NHR-49 acting in a receptor complex rather than as the direct OEA-binding receptor."
The ligand cavity is lined by hydrophobic residues plus polar residues including the conserved R132, implicated in fatty-acid head-group recognition.

"lined by hydrophobic residues plus polar residues including conserved **R132**, implicated in head-group interactions."
A 2021 proteomic-genetic study identified the nuclear factor RPC-2 as required both for LBP-8-mediated longevity and for robust nuclear localization of LBP-8, indicating that nuclear import (not export) drives the longevity effect.

"nuclear factor **RPC-2**, which was also necessary for robust nuclear localization of LBP-8; nuclear **import**, rather than export, was required for the longevity effect."
Within a broader inter-tissue lysosomal lipid-signaling network, LBP-3 and LBP-8 can have additive effects on lifespan, with nhr-49 required downstream of intestine-derived lysosomal lipid signaling.

"**LBP-3** and **LBP-8** can have additive effects on lifespan; **nhr-49** is required downstream of intestine-derived lysosomal lipid signaling to neuropeptide pathways."

Deep Research

Falcon

(lbp-8-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 2 artifacts 2026-05-30T10:59:52.697662

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000030 The requested visual content from the document is provided in the following figure panels: - **LBP-8 localization to lysosomes:** F (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.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Caenorhabditis elegans lbp-8 (UniProt O02324; WormBase locus T22G5.6)—functional annotation

1) Gene/protein identity verification (mandatory)

The C. elegans gene lbp-8 is explicitly mapped to the predicted locus T22G5.6 (“lbp-8 = T22G5.6”) in early nematode iFABP gene-family work, where it was classified as one of the nematode intracellular fatty acid-binding protein (iFABP) genes (lbp-1 through lbp-8). (Feb 2000; Molecular and Biochemical Parasitology; https://doi.org/10.1016/S0166-6851(99)00179-6) (plenefisch2000secretionofa pages 3-4)

Subsequent functional and structural studies on “LBP-8” in C. elegans consistently describe a fatty-acid/lipid-binding protein in the FABP/iLBP group that participates in lysosome-to-nucleus lipid signaling and longevity. (Jan 2015; Science; https://doi.org/10.1126/science.1258857) (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 4-10) (Jul 2019; Scientific Reports; https://doi.org/10.1038/s41598-019-46230-8) (tillman2019structuralcharacterizationof pages 1-2, tillman2019structuralcharacterizationof pages 2-3)

No evidence in the retrieved literature suggests this C. elegans lbp-8/T22G5.6 is conflated with a different organism’s “LBP-8”; the key mechanistic papers are explicitly in Caenorhabditis elegans. (folick2015lysosomalsignalingmolecules pages 1-3, plenefisch2000secretionofa pages 3-4)

2) Key concepts and definitions (current understanding)

2.1 What are FABPs/iLBPs/calycins?

Fatty acid-binding proteins (FABPs; also termed intracellular lipid-binding proteins, iLBPs) are small, soluble, non-enzymatic proteins that bind hydrophobic ligands (notably fatty acids and metabolites) and support intracellular lipid handling. A 2024 review synthesizes a consensus view that FABPs function as “sensors, conveyors and modulators”: they bind lipid metabolites, shuttle/sequester them, and modulate metabolic/signaling programs (including via nuclear receptor pathways). (Mar 2024; Journal of Cellular and Molecular Medicine; https://doi.org/10.1111/jcmm.17703) (agellon2024importanceoffatty pages 1-2, agellon2024importanceoffatty pages 5-6)

Structurally, FABPs belong to the calycin/lipocalin-like superfamily, sharing a conserved fold despite low sequence identity, including a β-barrel that encloses a ligand-binding cavity and an α-helical “lid/portal” implicated in ligand entry and membrane interactions. (Mar 2024; https://doi.org/10.1111/jcmm.17703) (agellon2024importanceoffatty pages 4-5, agellon2024importanceoffatty pages 2-4)

2.2 Implication for LBP-8 biochemical function

By this definition, LBP-8’s primary molecular function is expected to be ligand binding and intracellular transport/targeting of hydrophobic metabolites, not catalysis. The C. elegans literature directly supports this: LBP-8 is experimentally characterized as a lipid chaperone that translocates between lysosome and nucleus and drives transcriptional outputs via nuclear receptors. (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 4-10, tillman2019structuralcharacterizationof pages 1-2)

3) Molecular function: ligands (“substrates”), binding, and structural determinants

3.1 Ligand classes bound by LBP-8

LBP-8 binds long-chain fatty acids and fatty-acid derivatives. In the longevity-defining study, LBP-8 binds arachidonic acid (AA), ω-3 AA, dihomo-γ-linolenic acid (DGLA), and the fatty-acid ethanolamide oleoylethanolamide (OEA). In competitive binding assays, OEA bound LBP-8 with ~3× higher affinity than the tested fatty acids (relative comparison reported). (Jan 2015; Science; https://doi.org/10.1126/science.1258857) (folick2015lysosomalsignalingmolecules pages 3-4, folick2015lysosomalsignalingmolecules pages 4-10)

Structural/biochemical follow-up indicates a preference for monounsaturated fatty acyls, and shows that LBP-8 can co-purify with fatty acids and exchange ligands upon exposure to worm lipid extracts (e.g., enrichment for unsaturated species including oleic acid). (Jul 2019; Scientific Reports; https://doi.org/10.1038/s41598-019-46230-8) (tillman2019structuralcharacterizationof pages 3-6, tillman2019structuralcharacterizationof pages 9-10)

3.2 Structural basis for binding and trafficking

LBP-8’s crystal structure at 1.3 Å (PDB 6C1Z) shows the canonical FABP fold (helix-turn-helix lid + 10-stranded β-barrel) and defines a ligand cavity (reported surface area ~825 Å² and volume ~1170 Å³) lined by hydrophobic residues plus polar residues including conserved R132, implicated in head-group interactions. (Jul 2019; https://doi.org/10.1038/s41598-019-46230-8) (tillman2019structuralcharacterizationof pages 6-7, tillman2019structuralcharacterizationof pages 2-3)

A key feature of LBP-8 is a conserved, structural nuclear localization signal (NLS) formed by basic residues (K24/R33/K34). Deletion/mutation of this region abolishes nuclear translocation. (Jul 2019; https://doi.org/10.1038/s41598-019-46230-8) (tillman2019structuralcharacterizationof pages 3-6)

4) Biological role and pathways: lysosome-to-nucleus lipid signaling and longevity

4.1 Core pathway model

The central experimentally supported model is a lysosome-to-nucleus lipid signaling pathway:
1) Lysosomal lipolysis is stimulated via the lysosomal acid lipase LIPL-4.
2) LBP-8 levels increase and LBP-8 translocates from lysosomes to the nucleus.
3) LBP-8 carries lipid ligands (notably OEA) to nuclear hormone receptor machinery.
4) Nuclear receptors NHR-80 (direct OEA-binding) and NHR-49 (partner/cofactor) drive transcriptional programs (e.g., fatty-acid metabolism genes such as acs-2) that promote longevity. (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 3-4, folick2015lysosomalsignalingmolecules pages 4-10)

The 2015 Science paper provides causal genetic support: lbp-8 loss-of-function suppresses lipl-4-driven lifespan extension, while lbp-8 overexpression is sufficient to extend lifespan. (https://doi.org/10.1126/science.1258857) (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 4-10)

4.2 Quantitative phenotypes and transcriptional outputs

Key quantitative outcomes reported include:
- lipl-4 overexpression: ~55% mean lifespan increase. (folick2015lysosomalsignalingmolecules pages 1-3)
- lbp-8 overexpression: ~30% mean lifespan increase. (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 4-10)
- lbp-8 loss-of-function: reduces lipl-4-mediated lifespan extension by ~46% (reported as reduction of the extension). (folick2015lysosomalsignalingmolecules pages 4-10)
- Nuclear localization requirement: NLS-deleted LBP-8 is excluded from nuclei and shows little/no lifespan extension; transcription of acs-2 increases >10-fold in lbp-8 transgenics but not in NLS-deficient lbp-8 transgenics. (folick2015lysosomalsignalingmolecules pages 3-4, folick2015lysosomalsignalingmolecules pages 1-3)
- OEA signaling outputs: after 3 h of OEA-analogue treatment, lbp-8 transcription increased >4-fold and acs-2 >7-fold. (folick2015lysosomalsignalingmolecules pages 3-4)

The supporting visual evidence for localization, nuclear enrichment, and lifespan effects is shown in the retrieved figure panels from Folick et al. (LBP-8 lysosomal localization; nuclear localization; lifespan curves; ligand competition/binding assays). (folick2015lysosomalsignalingmolecules media 5ffc0917, folick2015lysosomalsignalingmolecules media 6d188de1, folick2015lysosomalsignalingmolecules media 8dce14ac)

4.3 Receptor/ligand specificity within the pathway

NHR-80 binds OEA directly with Kd = 7.841 µM (intrinsic fluorescence assay), whereas no OEA binding was detected for NHR-49 in that study, consistent with NHR-49 acting in a receptor complex rather than as the direct OEA-binding receptor. (Jan 2015; https://doi.org/10.1126/science.1258857) (folick2015lysosomalsignalingmolecules pages 3-4)

5) Subcellular and tissue localization (where LBP-8 acts)

5.1 Tissue restriction

In the primary longevity pathway study, lbp-8 expression was reported as exclusive to the intestine. (folick2015lysosomalsignalingmolecules pages 1-3)

5.2 Organelle and nuclear localization

LBP-8 is predominantly lysosomal in intestinal cells, co-localizing with lysosomal marker LMP-1, and also appears in nuclear and cytosolic fractions; lipl-4 overexpression enhances the nuclear fraction. (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 4-10)

The figure evidence retrieved from Folick et al. shows lysosomal co-localization and nuclear localization panels consistent with this dual localization and translocation model. (folick2015lysosomalsignalingmolecules media 5ffc0917, folick2015lysosomalsignalingmolecules media 6d188de1, folick2015lysosomalsignalingmolecules media 8dce14ac)

6) Recent developments (prioritizing 2023–2024) and current expert analysis

6.1 2023: NHR-49 as an aging/stress hub contextualizes lbp-8

A 2023 review positions NHR-49 as an essential regulator of stress resilience and healthy aging, describing its roles in fatty-acid catabolism/desaturation and its partnership with NHR-80 (heterodimerization) and cofactors such as MDT-15. While this review excerpt does not focus on LBP-8 directly, it strengthens the pathway-level interpretation that LBP-8’s longevity effect is mediated through an established NHR-49/NHR-80 lipid-metabolism transcriptional module. (Aug 2023; Frontiers in Physiology; https://doi.org/10.3389/fphys.2023.1241591) (doering2023nuclearhormonereceptor pages 1-2)

6.2 2024: FABPs as sensors/conveyors/modulators—supporting mechanistic interpretation

The 2024 FABP review provides a modern synthesis that FABPs can act as ligand-dependent nuclear signaling modulators, including in some contexts translocating to the nucleus to engage nuclear receptors. This framework aligns with LBP-8’s experimentally observed lysosome-to-nucleus translocation and receptor-linked transcriptional regulation. (Mar 2024; https://doi.org/10.1111/jcmm.17703) (agellon2024importanceoffatty pages 4-5, agellon2024importanceoffatty pages 5-6)

6.3 Note on 2023–2024 lbp-8-specific primary literature

Within the retrieved corpus, the most detailed LBP-8-specific mechanistic primary literature remains 2015 (Science) and 2019 (Scientific Reports), with additional mechanistic expansion in 2021 (preprint) and 2022 (Nature Cell Biology). The retrieved 2023–2024 sources primarily provide authoritative synthesis and context (NHR-49 biology; FABP family function) rather than new LBP-8-specific experiments. (doering2023nuclearhormonereceptor pages 1-2, agellon2024importanceoffatty pages 1-2)

7) Current applications and real-world implementations

1) Aging and lysosome-to-nucleus signaling model system: LBP-8 is used as a genetically tractable node to study how lysosomal lipolysis generates lipid signals that reprogram transcription to alter lifespan (lipl-4 → LBP-8 → NHR-49/NHR-80 → target genes). This pathway provides a concrete experimental system for “organelle communication” in aging. (folick2015lysosomalsignalingmolecules pages 4-10, tillman2019structuralcharacterizationof pages 1-2)

2) Structure-guided lipid-chaperone biology: The high-resolution LBP-8 structure (6C1Z) and defined NLS residues enable mutational tests of nuclear trafficking and ligand binding, and provide a scaffold for interpreting how sequence divergence preserves a conserved FABP fold with altered cavity chemistry. (tillman2019structuralcharacterizationof pages 2-3, tillman2019structuralcharacterizationof pages 6-7)

3) Inter-tissue lipid signaling context: In a broader lysosomal lipid signaling network, LBP-8 can show additive lifespan extension effects with LBP-3, helping dissect tissue-to-neuron communication (though LBP-3 is the more prominent inter-tissue transporter in that study). (Jun 2022; Nature Cell Biology; https://doi.org/10.1038/s41556-022-00926-8) (savini2022lysosomelipidsignalling pages 10-10)

8) Evidence summary table

The following evidence matrix summarizes identity, family, localization, ligands, pathways, quantitative phenotypes, and methods.

Claim/Aspect	Key findings with quantitative values when available	Primary source (year, journal) plus URL
Identity	lbp-8 in Caenorhabditis elegans is explicitly mapped to T22G5.6: “lbp-8 = T22G5.6”; classified as one of the nematode intracellular fatty acid-binding protein (iFABP) genes. Later work identifies LBP-8 as the C. elegans lipid/fatty-acid binding protein studied in longevity signaling. (plenefisch2000secretionofa pages 3-4, tillman2019structuralcharacterizationof pages 1-2)	Plenefisch et al. 2000, Molecular and Biochemical Parasitology. https://doi.org/10.1016/S0166-6851(99)00179-6; Tillman et al. 2019, Scientific Reports. https://doi.org/10.1038/s41598-019-46230-8
Family / structure	LBP-8 is an intracellular lipid-binding protein of the FABP/iLBP group within the calycin/lipocalin-like fold class; the 1.3 Å crystal structure (PDB 6C1Z) shows the canonical FABP architecture: N-terminal helix-turn-helix lid plus twisted 10-stranded antiparallel β-barrel. Protein is monomeric at ~16.4 kDa. The portal region supports a “collisional” FABP-like membrane interaction model. (tillman2019structuralcharacterizationof pages 1-2, tillman2019structuralcharacterizationof pages 2-3)	Tillman et al. 2019, Scientific Reports. https://doi.org/10.1038/s41598-019-46230-8
General FABP concept relevant to annotation	FABPs are small cytosolic lipid-binding proteins that act as sensors, conveyors, and modulators of hydrophobic metabolites; they typically bind fatty acids noncovalently and can shuttle ligands to membranes or nuclear receptors. These family properties support interpreting LBP-8 as a non-enzymatic lipid chaperone rather than an enzyme. (agellon2024importanceoffatty pages 1-2, agellon2024importanceoffatty pages 4-5, agellon2024importanceoffatty pages 2-4, agellon2024importanceoffatty pages 5-6)	Agellon 2024, Journal of Cellular and Molecular Medicine. https://doi.org/10.1111/jcmm.17703; Zhang et al. 2020, FEBS Open Bio. https://doi.org/10.1002/2211-5463.12840
Tissue expression	In the key longevity study, lbp-8 was exclusively expressed in the intestine. (folick2015lysosomalsignalingmolecules pages 1-3)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857
Subcellular localization	LBP-8 localizes predominantly to intestinal lysosomes (co-localization with LMP-1) and is also detected in nuclear and cytoplasmic fractions; lipl-4 overexpression enhances nuclear localization. In an LBP-8::GFP strain, 72–100% of worms showed nuclear enrichment in the first intestinal cell pair under control conditions; rpc-2 RNAi significantly reduced nuclear-enriched LBP-8. Visual evidence is in Folick Fig. 1G–I and 2A–G. (folick2015lysosomalsignalingmolecules pages 1-3, duffy2021lipidchaperonelbp8 pages 5-8, folick2015lysosomalsignalingmolecules pages 4-10, folick2015lysosomalsignalingmolecules media 5ffc0917)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857; Duffy et al. 2021, bioRxiv. https://doi.org/10.1101/2021.09.09.459489
Nuclear localization signal	LBP-8 contains an N-terminal / structural NLS. Basic residues K24, R33, K34 form a conserved 3D NLS analogous to mammalian FABP5. Deleting or mutating this region abolishes nuclear translocation, and NLS-deficient LBP-8 loses most longevity activity and fails to induce acs-2. (folick2015lysosomalsignalingmolecules pages 1-3, tillman2019structuralcharacterizationof pages 3-6)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857; Tillman et al. 2019, Scientific Reports. https://doi.org/10.1038/s41598-019-46230-8
Ligands / binding specificity	LBP-8 binds long-chain fatty acids and fatty-acid derivatives. Reported ligands include oleoylethanolamide (OEA), oleic acid, arachidonic acid (AA), ω-3 AA, and DGLA; competition assays showed OEA binds with ~3-fold higher affinity than the tested fatty acids. Structural/lipidomic work indicates preference for monounsaturated fatty acyls and identifies co-purifying palmitic (16:0) and oleic (18:1) acids from E. coli and, after exposure to worm extracts, enrichment for myristic (14:0) and unsaturated fatty acids including arachidonic (20:4), linoleic (18:2), and palmitoleic (16:1); oleic acid remained most abundant. (folick2015lysosomalsignalingmolecules pages 3-4, tillman2019structuralcharacterizationof pages 3-6, folick2015lysosomalsignalingmolecules pages 4-10, tillman2019structuralcharacterizationof pages 9-10, tillman2019structuralcharacterizationof pages 6-7)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857; Tillman et al. 2019, Scientific Reports. https://doi.org/10.1038/s41598-019-46230-8
Binding pocket features	The ligand cavity has solvent-accessible surface area ~825 Å² and volume ~1170 Å³; it is lined by hydrophobic residues (F19, F60, L65, F67, F73, F94, F110, T112, F134) plus polar residues including conserved R132 implicated in ligand head-group recognition. Interior/pocket mutants (Q121A, Y123A, R132A) altered ligand interactions. (tillman2019structuralcharacterizationof pages 6-7, tillman2019structuralcharacterizationof pages 8-9)	Tillman et al. 2019, Scientific Reports. https://doi.org/10.1038/s41598-019-46230-8
Primary molecular function	Best-supported annotation: LBP-8 is a non-enzymatic intracellular lipid chaperone that transfers lysosome-derived lipid signals to the nucleus. It does not catalyze a reaction; instead, it binds hydrophobic ligands and facilitates their delivery to transcriptional regulators. (folick2015lysosomalsignalingmolecules pages 1-3, tillman2019structuralcharacterizationof pages 2-3, agellon2024importanceoffatty pages 5-6, tillman2019structuralcharacterizationof pages 1-2)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857; Agellon 2024, Journal of Cellular and Molecular Medicine. https://doi.org/10.1111/jcmm.17703
Upstream pathway input	LIPL-4 lysosomal lipase induction upregulates lbp-8 and increases nuclear translocation of LBP-8. LIPL-4 overexpression elevates OEA and other fatty acids and extends mean lifespan by about 55%. LBP-8 is required for much of this effect. (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 4-10)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857
Downstream pathway / nuclear receptors	LBP-8 acts in a lysosome-to-nucleus lipid signaling pathway activating nuclear receptors NHR-49 and NHR-80. OEA binds NHR-80 directly with Kd = 7.841 µM; no OEA binding was detected for NHR-49, consistent with NHR-49 acting as a cofactor/partner. LBP-8 nuclear action increases transcription of targets such as acs-2; acs-2 induction exceeded 10-fold in lbp-8 transgenics but not in NLS-deficient transgenics. (folick2015lysosomalsignalingmolecules pages 3-4, folick2015lysosomalsignalingmolecules pages 4-10, tillman2019structuralcharacterizationof pages 1-2, doering2023nuclearhormonereceptor pages 1-2)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857; Doering et al. 2023, Frontiers in Physiology. https://doi.org/10.3389/fphys.2023.1241591
Nutrient / metabolic regulation	nhr-49 regulates lbp-8 expression in nutritional response pathways; earlier work reported ~4-fold compromised lbp-8 expression in fed nhr-49(nr2041) mutants. Review literature in 2023 emphasizes NHR-49 as a central regulator of lipid metabolism, stress resilience, and healthy aging, providing context for LBP-8’s placement in this pathway. (doering2023nuclearhormonereceptor pages 1-2)	van Gilst et al. 2005, PNAS. https://doi.org/10.1073/pnas.0506234102; Doering et al. 2023, Frontiers in Physiology. https://doi.org/10.3389/fphys.2023.1241591
Longevity phenotype	lbp-8 overexpression increases mean lifespan by about 30%. lbp-8 loss-of-function does not strongly alter WT lifespan but reduces lipl-4-mediated lifespan extension by about 46%. A transgenic LBP-8 lacking the NLS shows little or no lifespan extension. Visual lifespan evidence is in Folick Fig. 2I. (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 4-10, folick2015lysosomalsignalingmolecules media 5ffc0917)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857
OEA-related quantitative effects	OEA or an OEA analogue increased transcription of lbp-8 by >4-fold and acs-2 by >7-fold after 3 h treatment; direct OEA-analogue treatment prolonged WT lifespan but did not further extend lifespan in lipl-4 or lbp-8 transgenics. nape-1 loss suppressed lifespan extension in lipl-4 Tg and lbp-8 Tg by about half. (folick2015lysosomalsignalingmolecules pages 3-4)	Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857
Additional phenotypic / functional effects	A 2021 proteomic-genetic study reported that LBP-8 overexpression reduced fat storage and upregulated mitochondrial β-oxidation genes; in a screen, day-17 survival averaged 56% alive vs 38% WT for the overexpression strain under EV controls. (duffy2021lipidchaperonelbp8 pages 1-5, duffy2021lipidchaperonelbp8 pages 5-8)	Duffy et al. 2021, bioRxiv. https://doi.org/10.1101/2021.09.09.459489
Protein partners / nuclear retention	Anti-FLAG IP-MS identified 45 candidate LBP-8 interactors (≥50-fold enrichment cutoff; replicate correlations R = 0.89–0.94). Several genes were required for LBP-8-mediated longevity, especially the nuclear factor RPC-2, which was also necessary for robust nuclear localization of LBP-8; nuclear import, rather than export, was required for the longevity effect. (duffy2021lipidchaperonelbp8 pages 1-5, duffy2021lipidchaperonelbp8 pages 5-8, duffy2021lipidchaperonelbp8 pages 18-27)	Duffy et al. 2021, bioRxiv. https://doi.org/10.1101/2021.09.09.459489
Relationship to inter-tissue lipid signaling	In a broader lysosomal lipid-signaling network, LBP-3 and LBP-8 can have additive effects on lifespan; nhr-49 is required downstream of intestine-derived lysosomal lipid signaling to neuropeptide pathways. However, lbp-8 alone had minimal effect on some neuropeptide transcripts compared with lbp-3. (savini2022lysosomelipidsignalling pages 10-10)	Savini et al. 2022, Nature Cell Biology. https://doi.org/10.1038/s41556-022-00926-8
Key methods supporting annotation	Gene-family mapping / sequence inspection; transgenics and mutant analysis; RNAi; lysosome marker co-localization (LMP-1); nuclear/cytoplasmic fractionation; lifespan assays; fluorescence competition binding; intrinsic fluorescence for receptor binding; X-ray crystallography (1.3 Å, PDB 6C1Z); 1,8-ANS binding assays; differential scanning fluorimetry; circular dichroism; lipid extraction and mass spectrometry; anti-FLAG IP-MS proteomics. (folick2015lysosomalsignalingmolecules pages 1-3, folick2015lysosomalsignalingmolecules pages 3-4, duffy2021lipidchaperonelbp8 pages 5-8, tillman2019structuralcharacterizationof pages 2-3, tillman2019structuralcharacterizationof pages 10-11, folick2015lysosomalsignalingmolecules media 5ffc0917)	Plenefisch et al. 2000, Molecular and Biochemical Parasitology. https://doi.org/10.1016/S0166-6851(99)00179-6; Folick et al. 2015, Science. https://doi.org/10.1126/science.1258857; Tillman et al. 2019, Scientific Reports. https://doi.org/10.1038/s41598-019-46230-8; Duffy et al. 2021, bioRxiv. https://doi.org/10.1101/2021.09.09.459489

Table: This table summarizes identity, molecular function, localization, pathway placement, ligands, phenotypes, and methods for C. elegans LBP-8 using only the cited evidence sources. It is useful as a compact evidence matrix for functional annotation of lbp-8/T22G5.6 (UniProt O02324).

9) Concise functional annotation (recommended)

lbp-8 (T22G5.6; UniProt O02324) encodes an intracellular fatty-acid binding protein (FABP/iLBP; calycin/lipocalin-like fold) expressed in the intestine, localized primarily to lysosomes but capable of nuclear translocation via a conserved structural NLS. LBP-8 binds long-chain lipids including OEA (higher relative affinity vs tested fatty acids) and functions as a lysosome-to-nucleus lipid chaperone that engages the NHR-49/NHR-80 transcriptional module (with direct OEA binding shown for NHR-80, Kd ~7.841 µM), thereby inducing lipid-metabolic transcriptional programs (e.g., acs-2) and promoting longevity when overexpressed. (folick2015lysosomalsignalingmolecules pages 4-10, folick2015lysosomalsignalingmolecules pages 3-4, tillman2019structuralcharacterizationof pages 3-6, plenefisch2000secretionofa pages 3-4)

References

(plenefisch2000secretionofa pages 3-4): John Plenefisch, Hong Xiao, Baisong Mei, Jinming Geng, Patricia R Komuniecki, and Richard Komuniecki. Secretion of a novel class of ifabps in nematodes: coordinate use of the ascaris/caenorhabditis model systems. Molecular and biochemical parasitology, 105 2:223-36, Feb 2000. URL: https://doi.org/10.1016/s0166-6851(99)00179-6, doi:10.1016/s0166-6851(99)00179-6. This article has 57 citations and is from a peer-reviewed journal.
(folick2015lysosomalsignalingmolecules pages 1-3): Andrew Folick, Holly D. Oakley, Yong Yu, Eric H. Armstrong, Manju Kumari, Lucas Sanor, David D. Moore, Eric A. Ortlund, Rudolf Zechner, and Meng C. Wang. Lysosomal signaling molecules regulate longevity in caenorhabditis elegans. Science, 347:83-86, Jan 2015. URL: https://doi.org/10.1126/science.1258857, doi:10.1126/science.1258857. This article has 316 citations and is from a highest quality peer-reviewed journal.
(folick2015lysosomalsignalingmolecules pages 4-10): Andrew Folick, Holly D. Oakley, Yong Yu, Eric H. Armstrong, Manju Kumari, Lucas Sanor, David D. Moore, Eric A. Ortlund, Rudolf Zechner, and Meng C. Wang. Lysosomal signaling molecules regulate longevity in caenorhabditis elegans. Science, 347:83-86, Jan 2015. URL: https://doi.org/10.1126/science.1258857, doi:10.1126/science.1258857. This article has 316 citations and is from a highest quality peer-reviewed journal.
(tillman2019structuralcharacterizationof pages 1-2): Matthew C. Tillman, Manoj Khadka, Jonathon Duffy, Meng C. Wang, and Eric A. Ortlund. Structural characterization of life-extending caenorhabditis elegans lipid binding protein 8. Scientific Reports, Jul 2019. URL: https://doi.org/10.1038/s41598-019-46230-8, doi:10.1038/s41598-019-46230-8. This article has 15 citations and is from a peer-reviewed journal.
(tillman2019structuralcharacterizationof pages 2-3): Matthew C. Tillman, Manoj Khadka, Jonathon Duffy, Meng C. Wang, and Eric A. Ortlund. Structural characterization of life-extending caenorhabditis elegans lipid binding protein 8. Scientific Reports, Jul 2019. URL: https://doi.org/10.1038/s41598-019-46230-8, doi:10.1038/s41598-019-46230-8. This article has 15 citations and is from a peer-reviewed journal.
(agellon2024importanceoffatty pages 1-2): Luis B. Agellon. Importance of fatty acid binding proteins in cellular function and organismal metabolism. Journal of Cellular and Molecular Medicine, Mar 2024. URL: https://doi.org/10.1111/jcmm.17703, doi:10.1111/jcmm.17703. This article has 27 citations and is from a peer-reviewed journal.
(agellon2024importanceoffatty pages 5-6): Luis B. Agellon. Importance of fatty acid binding proteins in cellular function and organismal metabolism. Journal of Cellular and Molecular Medicine, Mar 2024. URL: https://doi.org/10.1111/jcmm.17703, doi:10.1111/jcmm.17703. This article has 27 citations and is from a peer-reviewed journal.
(agellon2024importanceoffatty pages 4-5): Luis B. Agellon. Importance of fatty acid binding proteins in cellular function and organismal metabolism. Journal of Cellular and Molecular Medicine, Mar 2024. URL: https://doi.org/10.1111/jcmm.17703, doi:10.1111/jcmm.17703. This article has 27 citations and is from a peer-reviewed journal.
(agellon2024importanceoffatty pages 2-4): Luis B. Agellon. Importance of fatty acid binding proteins in cellular function and organismal metabolism. Journal of Cellular and Molecular Medicine, Mar 2024. URL: https://doi.org/10.1111/jcmm.17703, doi:10.1111/jcmm.17703. This article has 27 citations and is from a peer-reviewed journal.
(folick2015lysosomalsignalingmolecules pages 3-4): Andrew Folick, Holly D. Oakley, Yong Yu, Eric H. Armstrong, Manju Kumari, Lucas Sanor, David D. Moore, Eric A. Ortlund, Rudolf Zechner, and Meng C. Wang. Lysosomal signaling molecules regulate longevity in caenorhabditis elegans. Science, 347:83-86, Jan 2015. URL: https://doi.org/10.1126/science.1258857, doi:10.1126/science.1258857. This article has 316 citations and is from a highest quality peer-reviewed journal.
(tillman2019structuralcharacterizationof pages 3-6): Matthew C. Tillman, Manoj Khadka, Jonathon Duffy, Meng C. Wang, and Eric A. Ortlund. Structural characterization of life-extending caenorhabditis elegans lipid binding protein 8. Scientific Reports, Jul 2019. URL: https://doi.org/10.1038/s41598-019-46230-8, doi:10.1038/s41598-019-46230-8. This article has 15 citations and is from a peer-reviewed journal.
(tillman2019structuralcharacterizationof pages 9-10): Matthew C. Tillman, Manoj Khadka, Jonathon Duffy, Meng C. Wang, and Eric A. Ortlund. Structural characterization of life-extending caenorhabditis elegans lipid binding protein 8. Scientific Reports, Jul 2019. URL: https://doi.org/10.1038/s41598-019-46230-8, doi:10.1038/s41598-019-46230-8. This article has 15 citations and is from a peer-reviewed journal.
(tillman2019structuralcharacterizationof pages 6-7): Matthew C. Tillman, Manoj Khadka, Jonathon Duffy, Meng C. Wang, and Eric A. Ortlund. Structural characterization of life-extending caenorhabditis elegans lipid binding protein 8. Scientific Reports, Jul 2019. URL: https://doi.org/10.1038/s41598-019-46230-8, doi:10.1038/s41598-019-46230-8. This article has 15 citations and is from a peer-reviewed journal.
(folick2015lysosomalsignalingmolecules media 5ffc0917): Andrew Folick, Holly D. Oakley, Yong Yu, Eric H. Armstrong, Manju Kumari, Lucas Sanor, David D. Moore, Eric A. Ortlund, Rudolf Zechner, and Meng C. Wang. Lysosomal signaling molecules regulate longevity in caenorhabditis elegans. Science, 347:83-86, Jan 2015. URL: https://doi.org/10.1126/science.1258857, doi:10.1126/science.1258857. This article has 316 citations and is from a highest quality peer-reviewed journal.
(folick2015lysosomalsignalingmolecules media 6d188de1): Andrew Folick, Holly D. Oakley, Yong Yu, Eric H. Armstrong, Manju Kumari, Lucas Sanor, David D. Moore, Eric A. Ortlund, Rudolf Zechner, and Meng C. Wang. Lysosomal signaling molecules regulate longevity in caenorhabditis elegans. Science, 347:83-86, Jan 2015. URL: https://doi.org/10.1126/science.1258857, doi:10.1126/science.1258857. This article has 316 citations and is from a highest quality peer-reviewed journal.
(folick2015lysosomalsignalingmolecules media 8dce14ac): Andrew Folick, Holly D. Oakley, Yong Yu, Eric H. Armstrong, Manju Kumari, Lucas Sanor, David D. Moore, Eric A. Ortlund, Rudolf Zechner, and Meng C. Wang. Lysosomal signaling molecules regulate longevity in caenorhabditis elegans. Science, 347:83-86, Jan 2015. URL: https://doi.org/10.1126/science.1258857, doi:10.1126/science.1258857. This article has 316 citations and is from a highest quality peer-reviewed journal.
(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.
(savini2022lysosomelipidsignalling pages 10-10): Marzia Savini, Andrew Folick, Yi-Tang Lee, Feng Jin, André Cuevas, Matthew C. Tillman, Jonathon D. Duffy, Qian Zhao, Isaiah A. Neve, Pei-Wen Hu, Yong Yu, Qinghao Zhang, Youqiong Ye, William B. Mair, Jin Wang, Leng Han, Eric A. Ortlund, and Meng C. Wang. Lysosome lipid signalling from the periphery to neurons regulates longevity. Nature Cell Biology, 24:906-916, Jun 2022. URL: https://doi.org/10.1038/s41556-022-00926-8, doi:10.1038/s41556-022-00926-8. This article has 94 citations and is from a highest quality peer-reviewed journal.
(duffy2021lipidchaperonelbp8 pages 5-8): Jonathon Duffy, Qinghao Zhang, Sung Y. Jung, and Meng C. Wang. Lipid chaperone lbp-8 coordinates with nuclear factors to promote longevity in caenorhabditis elegans. bioRxiv, Sep 2021. URL: https://doi.org/10.1101/2021.09.09.459489, doi:10.1101/2021.09.09.459489. This article has 1 citations.
(tillman2019structuralcharacterizationof pages 8-9): Matthew C. Tillman, Manoj Khadka, Jonathon Duffy, Meng C. Wang, and Eric A. Ortlund. Structural characterization of life-extending caenorhabditis elegans lipid binding protein 8. Scientific Reports, Jul 2019. URL: https://doi.org/10.1038/s41598-019-46230-8, doi:10.1038/s41598-019-46230-8. This article has 15 citations and is from a peer-reviewed journal.
(duffy2021lipidchaperonelbp8 pages 1-5): Jonathon Duffy, Qinghao Zhang, Sung Y. Jung, and Meng C. Wang. Lipid chaperone lbp-8 coordinates with nuclear factors to promote longevity in caenorhabditis elegans. bioRxiv, Sep 2021. URL: https://doi.org/10.1101/2021.09.09.459489, doi:10.1101/2021.09.09.459489. This article has 1 citations.
(duffy2021lipidchaperonelbp8 pages 18-27): Jonathon Duffy, Qinghao Zhang, Sung Y. Jung, and Meng C. Wang. Lipid chaperone lbp-8 coordinates with nuclear factors to promote longevity in caenorhabditis elegans. bioRxiv, Sep 2021. URL: https://doi.org/10.1101/2021.09.09.459489, doi:10.1101/2021.09.09.459489. This article has 1 citations.
(tillman2019structuralcharacterizationof pages 10-11): Matthew C. Tillman, Manoj Khadka, Jonathon Duffy, Meng C. Wang, and Eric A. Ortlund. Structural characterization of life-extending caenorhabditis elegans lipid binding protein 8. Scientific Reports, Jul 2019. URL: https://doi.org/10.1038/s41598-019-46230-8, doi:10.1038/s41598-019-46230-8. This article has 15 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

plenefisch2000secretionofa pages 3-4
tillman2019structuralcharacterizationof pages 3-6
folick2015lysosomalsignalingmolecules pages 1-3
folick2015lysosomalsignalingmolecules pages 4-10
folick2015lysosomalsignalingmolecules pages 3-4
doering2023nuclearhormonereceptor pages 1-2
savini2022lysosomelipidsignalling pages 10-10
tillman2019structuralcharacterizationof pages 1-2
tillman2019structuralcharacterizationof pages 2-3
agellon2024importanceoffatty pages 1-2
agellon2024importanceoffatty pages 5-6
agellon2024importanceoffatty pages 4-5
agellon2024importanceoffatty pages 2-4
tillman2019structuralcharacterizationof pages 9-10
tillman2019structuralcharacterizationof pages 6-7
tillman2019structuralcharacterizationof pages 8-9
tillman2019structuralcharacterizationof pages 10-11
https://doi.org/10.1016/S0166-6851(99
https://doi.org/10.1126/science.1258857
https://doi.org/10.1038/s41598-019-46230-8
https://doi.org/10.1111/jcmm.17703
https://doi.org/10.3389/fphys.2023.1241591
https://doi.org/10.1038/s41556-022-00926-8
https://doi.org/10.1111/jcmm.17703;
https://doi.org/10.1002/2211-5463.12840
https://doi.org/10.1126/science.1258857;
https://doi.org/10.1101/2021.09.09.459489
https://doi.org/10.1073/pnas.0506234102;
https://doi.org/10.1038/s41598-019-46230-8;
https://doi.org/10.1016/s0166-6851(99
https://doi.org/10.1126/science.1258857,
https://doi.org/10.1038/s41598-019-46230-8,
https://doi.org/10.1111/jcmm.17703,
https://doi.org/10.3389/fphys.2023.1241591,
https://doi.org/10.1038/s41556-022-00926-8,
https://doi.org/10.1101/2021.09.09.459489,

📚 Additional Documentation

Notes

(lbp-8-notes.md)

lbp-8 Research Notes

Gene Overview

lbp-8 (T22G5.6) encodes a fatty acid-binding protein (FABP) homolog that functions as a lysosomal lipid chaperone in C. elegans. It is a key mediator in the lysosome-to-nucleus retrograde lipid signaling pathway linking lysosomal lipid metabolism to nuclear transcription and longevity.

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

LBP-8 shuttles lipid signals generated by the lysosomal lipase LIPL-4 to the nucleus, where they activate transcription factors NHR-49 and NHR-80 to promote longevity PMID:25554789.

Structural Features

Crystal structure solved at 1.3 Å (PDB: 6C1Z) PMID:31292465
Adopts typical lipocalin/FABP fold: beta barrel capped by alpha helical lid
Monomer in solution (16.4 kDa)
Interior cavity: 825 Å² surface area, 1170 Å³ volume
Contains structurally conserved nuclear localization signal (NLS) in portal region (K24, R33, K34)
Classified as a "collisional" FABP - interacts with membranes via hydrophobic patch in alpha helical lid

Lipid Binding

Binds oleic acid and OEA with high and similar affinity PMID:31292465
OEA binding affinity ~3x higher than for C20 fatty acids (AA, DGLA, omega-3 AA) PMID:25554789
Also binds arachidonic acid, DGLA, palmitic acid, linoleic acid, and other long-chain fatty acids PMID:31292465
Does NOT bind bile acids (cholic, taurocholic, glycocholic) despite pocket size similarity to FABP6 PMID:31292465
R132 is the key conserved residue for fatty acid head group interaction PMID:31292465
Oleic acid destabilizes LBP-8 (Tm decreased ~4°C); OEA has no effect on Tm PMID:31292465

Subcellular Localization

Expressed exclusively in the intestine PMID:25554789
Predominantly localized to intestinal lysosomes PMID:25554789
Partial nuclear localization enhanced in lipl-4 Tg animals PMID:25554789
NLS deletion abolishes nuclear localization and lifespan extension PMID:25554789

Longevity Function

LBP-8 overexpression extends lifespan by ~30% PMID:25554789
Nuclear localization required for longevity effect (no NLS version shows little extension) PMID:25554789
LBP-8 depletion or deletion (lbp-8(rax1)) suppresses lipl-4 Tg longevity PMID:25554789
Longevity requires NHR-49 and NHR-80 PMID:25554789

Regulation

lbp-8 is exclusively upregulated (of 9 FABP homologs) in lipl-4 Tg animals PMID:25554789
Not upregulated in lipl-4 Tg no SP strain PMID:25554789
OEA and its analogue induce lbp-8 transcription in wild-type via NHR-49/NHR-80 PMID:25554789
Positive feedback loop: LIPL-4 → OEA → NHR-49/NHR-80 → lbp-8 transcription

Early Characterization

Initially characterized as part of a novel class of intracellular FABPs in nematodes PMID:10693745

📄 View Raw YAML

id: O02324
gene_symbol: lbp-8
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  LBP-8 is a lysosomal lipid chaperone belonging to the fatty acid-binding protein
  (FABP) family.
  It functions as an intracellular lipid shuttle, binding long-chain fatty acids (especially
  oleic acid)
  and oleoylethanolamide (OEA) with high affinity and transporting them from lysosomes
  to the nucleus.
  In the nucleus, LBP-8-delivered lipid signals activate the nuclear hormone receptors
  NHR-49 and NHR-80,
  promoting transcription of genes involved in mitochondrial beta-oxidation (e.g.
  acs-2) and longevity.
  LBP-8 is part of the LIPL-4-initiated lysosome-to-nucleus retrograde lipid signaling
  pathway that
  extends lifespan. LBP-8 overexpression extends lifespan by approximately 30%, and
  this effect requires
  its structurally conserved nuclear localization signal (NLS) in the N-terminal helix-turn-helix
  motif.
  LBP-8 is expressed exclusively in the intestine. The crystal structure at 1.3 angstrom
  resolution
  (PDB 6C1Z) confirms it is a monomer with a typical lipocalin fold and a large interior
  cavity
  capable of accommodating diverse fatty acids.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      LBP-8 nuclear localization is well-established by direct experimental evidence
      (PMID:25554789).
      Folick et al. demonstrated partial nuclear localization of LBP-8 in the intestine,
      enhanced
      upon LIPL-4 overexpression. LBP-8 was detected in nuclear fractions of total
      worm lysate.
      The IBA annotation is consistent with all available evidence.
    action: ACCEPT
    reason: >-
      Nuclear localization is a core feature of LBP-8 function, demonstrated by fluorescent
      tagging
      and subcellular fractionation (PMID:25554789). Tillman et al. (PMID:31292465)
      further identified
      a structurally conserved NLS (K24, R33, K34) required for nuclear translocation.
      The IBA
      annotation is phylogenetically sound and experimentally validated.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        We also detected partial nuclear localization of LBP-8 in the intestine, which
        was
        enhanced in lipl-4 Tg animals
    - reference_id: PMID:31292465
      supporting_text: >-
        we determined the first 1.3 Å high-resolution structure of this life-extending
        protein LBP-8, which allowed us to identify a structurally conserved nuclear
        localization signal
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        conserved, structural **nuclear localization signal (NLS)** formed by basic residues (K24/R33/K34). Deletion/mutation of this region abolishes nuclear translocation.
      reference_section_type: RESULTS
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      LBP-8 is an intracellular lipid-binding protein and, as a soluble FABP, would
      be expected to
      be present in the cytosol. Folick et al. (PMID:25554789) detected LBP-8 in cytoplasmic
      fractions.
      The IBA annotation is phylogenetically reasonable for FABPs.
    action: ACCEPT
    reason: >-
      Cytosolic localization is expected for a soluble FABP family member. LBP-8 was
      detected in
      cytoplasmic fractions (PMID:25554789), and as a lipid shuttle between lysosomes
      and nucleus,
      it transits through the cytosol. The IBA annotation is consistent with evidence.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        LBP-8 contains an N-terminal nuclear localization signal (NLS) ... and was
        present
        in both cytoplasmic and nuclear fractions of total worm lysate
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 is predominantly **lysosomal in intestinal cells**, co-localizing with lysosomal marker **LMP-1**, and also appears in nuclear and cytosolic fractions
      reference_section_type: RESULTS
- term:
    id: GO:0005504
    label: fatty acid binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      LBP-8 fatty acid binding is well-established experimentally. Folick et al. (PMID:25554789)
      showed
      LBP-8 binds arachidonic acid, omega-3 arachidonic acid, DGLA, and OEA. Tillman
      et al.
      (PMID:31292465) used mass spectrometry to identify a broad range of fatty acids
      co-purifying
      with LBP-8, with preference for monounsaturated fatty acids. The IBA annotation
      is appropriate
      and at the right level of specificity for the FABP family.
    action: ACCEPT
    reason: >-
      Fatty acid binding is the central molecular function of LBP-8 as a FABP family
      member. Extensive
      experimental validation by both fluorescence-based binding assays (PMID:25554789)
      and LC/MS
      (PMID:31292465). The IBA annotation is at an appropriate level.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:31292465
      supporting_text: >-
        we described the range of fatty acids LBP-8 is capable of binding and show
        that it
        binds to life-extending ligands in worms such as oleic acid and
        oleoylethanolamide with high affinity
    - reference_id: PMID:25554789
      supporting_text: >-
        all four lipids bound to LBP-8, and the binding affinity of OEA for LBP-8
        was 3 times
        higher than that of the fatty acids
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 binds long-chain fatty acids and fatty-acid derivatives.
      reference_section_type: RESULTS
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        Reported ligands include **oleoylethanolamide (OEA)**, **oleic acid**, **arachidonic acid (AA)**, **ω-3 AA**, and **DGLA**; competition assays showed **OEA binds with ~3-fold higher affinity** than the tested fatty acids.
      reference_section_type: RESULTS
- term:
    id: GO:0015908
    label: fatty acid transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      LBP-8 functions as an intracellular fatty acid transporter, shuttling lipid
      signals from
      lysosomes to the nucleus (PMID:25554789). The IBA annotation for fatty acid
      transport is
      phylogenetically sound and at the right level of specificity.
    action: ACCEPT
    reason: >-
      LBP-8 is an intracellular lipid chaperone that transports fatty acids and their
      derivatives
      from lysosomes to the nucleus (PMID:25554789). This is its core biological process.
      The IBA
      annotation at the level of fatty acid transport is appropriate.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals
        to the nucleus
    - reference_id: PMID:31292465
      supporting_text: >-
        supporting the role of LBP-8 as a shuttling protein for monounsaturated fatty
        acids
        and their derivatives
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 carries lipid ligands (notably **OEA**) to nuclear hormone receptor machinery
      reference_section_type: RESULTS
- term:
    id: GO:0005504
    label: fatty acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for fatty acid binding via ARBA machine learning. This is consistent
      with the
      experimentally validated function of LBP-8 as a FABP. Duplicates the IBA annotation
      but is
      acceptable as an independent computational prediction.
    action: ACCEPT
    reason: >-
      The IEA annotation is correct and consistent with extensive experimental evidence
      for fatty
      acid binding by LBP-8 (PMID:25554789, PMID:31292465). It is a valid independent
      computational
      prediction that agrees with the IBA annotation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for nuclear localization based on UniProt subcellular location
      mapping.
      Consistent with IDA evidence from PMID:25554789 showing LBP-8 in the nucleus.
    action: ACCEPT
    reason: >-
      The IEA annotation correctly reflects the experimentally determined nuclear
      localization
      of LBP-8 (PMID:25554789). UniProt mapping is appropriate here.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for lysosomal localization based on UniProt subcellular location
      mapping.
      Consistent with IDA evidence from PMID:25554789 showing LBP-8 localization to
      lysosomes.
    action: ACCEPT
    reason: >-
      The IEA annotation correctly reflects the experimentally determined lysosomal
      localization
      of LBP-8. Folick et al. (PMID:25554789) showed FLAG- and mCherry-tagged LBP-8
      predominantly
      localized to intestinal lysosomes.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        Both FLAG- and mCherry-tagged LBP-8 proteins were predominantly localized
        to
        intestinal lysosomes
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 is predominantly **lysosomal in intestinal cells**, co-localizing with lysosomal marker **LMP-1**
      reference_section_type: RESULTS
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for lipid binding based on InterPro domain mapping. LBP-8 contains
      the FABP
      domain (IPR000463). This is a broader parent term of fatty acid binding (GO:0005504),
      which
      is already annotated with more specific evidence. The IEA is acceptable as it
      captures the
      InterPro-based prediction, though it is less specific than the IBA/IDA annotations.
    action: ACCEPT
    reason: >-
      The IEA annotation is correct but broader than the more specific fatty acid
      binding annotations
      already present. It is acceptable as an independent InterPro-based prediction.
      LBP-8 binds
      diverse lipids including fatty acids and OEA (PMID:25554789, PMID:31292465).
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 binds long-chain fatty acids and fatty-acid derivatives.
      reference_section_type: RESULTS
- term:
    id: GO:0070538
    label: oleic acid binding
  evidence_type: IDA
  original_reference_id: PMID:31292465
  review:
    summary: >-
      Tillman et al. (PMID:31292465) directly demonstrated oleic acid binding to LBP-8
      using
      competitive fluorescence-based binding assays and mass spectrometry. Oleic acid
      was the most
      abundant fatty acid co-purifying with LBP-8 from both E. coli and C. elegans
      lipid extracts.
      Oleic acid and OEA had similar high-affinity Ki values. This is a well-supported
      IDA annotation.
    action: ACCEPT
    reason: >-
      Oleic acid binding is directly demonstrated by competitive fluorescence binding
      assays and
      LC/MS co-purification in PMID:31292465. Oleic acid was the most abundant fatty
      acid bound to
      LBP-8 (28.93% from C. elegans extracts, 35.72% from E. coli). This specific
      binding activity
      is core to LBP-8 function.
    supported_by:
    - reference_id: PMID:31292465
      supporting_text: >-
        A fluorescence-based ligand binding assay was used to compare the affinity
        of oleic
        acid and OEA, and both had very similar Ki's, suggesting oleic acid, along
        with OEA,
        are high affinity ligands of LBP-8
    - reference_id: PMID:31292465
      supporting_text: >-
        While the relative percentage of oleic acid decreased, it was still the most
        abundant
        fatty acid that bound to LBP-8
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        identifies co-purifying **palmitic (16:0)** and **oleic (18:1)** acids from *E. coli* and, after exposure to worm extracts, enrichment for **myristic (14:0)** and unsaturated fatty acids including **arachidonic (20:4)**, **linoleic (18:2)**, and **palmitoleic (16:1)**; oleic acid remained most abundant.
      reference_section_type: RESULTS
- term:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:25554789
  review:
    summary: >-
      GO:0005324 (long-chain fatty acid transporter activity) is defined as enabling
      transfer of
      long-chain fatty acids from one side of a membrane to the other. LBP-8 is not
      a transmembrane
      transporter. It is a soluble intracellular lipid chaperone that shuttles fatty
      acids between
      cellular compartments (lysosomes to nucleus) through the cytosol. Folick et
      al. (PMID:25554789)
      showed LBP-8 translocates from lysosomes to the nucleus carrying lipid signals,
      but this is
      intracellular lipid transfer, not transmembrane transport. The IMP evidence
      is based on
      lbp-8 mutant phenotypes affecting lipid signaling, not transmembrane transport
      assays.
    action: MODIFY
    reason: >-
      The term GO:0005324 (long-chain fatty acid transporter activity) specifically
      describes
      transmembrane transport activity, which is not the mechanism by which LBP-8
      functions. LBP-8
      is a soluble lipid chaperone that binds fatty acids and shuttles them intracellularly
      (PMID:25554789, PMID:31292465). A more appropriate MF term would be lipid transfer
      activity
      (GO:0120013), defined as removing a lipid from a membrane, transporting it through
      the aqueous
      phase in a hydrophobic pocket, and delivering it to an acceptor. This matches
      the LBP-8
      mechanism precisely.
    proposed_replacement_terms:
    - id: GO:0120013
      label: lipid transfer activity
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals
        to the nucleus
    - reference_id: PMID:31292465
      supporting_text: >-
        certain human FABPs have been shown to shuttle nuclear receptor ligands into
        the
        nucleus to regulate nuclear receptor transcription
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 is a **non-enzymatic intracellular lipid chaperone** that transfers lysosome-derived lipid signals to the nucleus. It does **not catalyze a reaction**; instead, it binds hydrophobic ligands and facilitates their delivery to transcriptional regulators.
      reference_section_type: RESULTS
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25554789
  review:
    summary: >-
      Folick et al. (PMID:25554789) directly showed nuclear localization of LBP-8
      in the intestine
      using fluorescent tagging (mCherry, FLAG) and subcellular fractionation. Nuclear
      localization
      was enhanced in LIPL-4 overexpressing animals. LBP-8 was present in nuclear
      fractions. Deletion
      of the NLS abolished nuclear localization and lifespan extension.
    action: ACCEPT
    reason: >-
      Nuclear localization is a core feature of LBP-8 function, directly demonstrated
      by IDA
      evidence in PMID:25554789. LBP-8 translocates to the nucleus to deliver lipid
      signals to
      nuclear hormone receptors NHR-49 and NHR-80.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        We also detected partial nuclear localization of LBP-8 in the intestine, which
        was
        enhanced in lipl-4 Tg animals
    - reference_id: PMID:25554789
      supporting_text: >-
        LBP-8 contains an N-terminal nuclear localization signal (NLS) ... and was
        present
        in both cytoplasmic and nuclear fractions of total worm lysate
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 is experimentally characterized as a lipid chaperone that translocates between lysosome and nucleus and drives transcriptional outputs via nuclear receptors.
      reference_section_type: RESULTS
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:25554789
  review:
    summary: >-
      Folick et al. (PMID:25554789) directly showed LBP-8 localization to intestinal
      lysosomes
      using FLAG and mCherry tagging with colocalization studies. LBP-8 was predominantly
      found
      at lysosomes under basal conditions, with nuclear translocation enhanced upon
      LIPL-4
      overexpression.
    action: ACCEPT
    reason: >-
      Lysosomal localization is a core feature of LBP-8, demonstrated by direct fluorescent
      microscopy and colocalization in PMID:25554789. This localization is central
      to LBP-8's
      role in the lysosome-to-nucleus signaling pathway.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        Both FLAG- and mCherry-tagged LBP-8 proteins were predominantly localized
        to
        intestinal lysosomes
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 is predominantly **lysosomal in intestinal cells**, co-localizing with lysosomal marker **LMP-1**, and also appears in nuclear and cytosolic fractions; **lipl-4** overexpression enhances the nuclear fraction.
      reference_section_type: RESULTS
- term:
    id: GO:0015909
    label: long-chain fatty acid transport
  evidence_type: IMP
  original_reference_id: PMID:25554789
  review:
    summary: >-
      Folick et al. (PMID:25554789) demonstrated that LBP-8 is required for LIPL-4-mediated
      longevity signaling, which involves transport of lipid signals (including long-chain
      fatty
      acids and OEA) from lysosomes to the nucleus. The IMP evidence comes from lbp-8
      loss-of-function
      suppressing lipl-4-mediated lifespan extension. While the biological process
      annotation is
      broadly correct, the transport is intracellular rather than across membranes.
    action: ACCEPT
    reason: >-
      Long-chain fatty acid transport is an appropriate biological process term for
      LBP-8. The
      GO:0015909 definition includes movement "within a cell", which accurately describes
      LBP-8's
      intracellular lipid shuttling function. The IMP evidence is sound: lbp-8 mutants
      suppress
      lipl-4-mediated longevity and lipid signaling (PMID:25554789).
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        Both RNA interference (RNAi)-mediated depletion of LBP-8 and a newly isolated
        deletion
        mutant, lbp-8(rax1), suppressed the lifespan extension in lipl-4 Tg animals
    - reference_id: PMID:31292465
      supporting_text: >-
        supporting the role of LBP-8 as a shuttling protein for monounsaturated fatty
        acids
        and their derivatives
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        functions as a **lysosome-to-nucleus lipid chaperone**
      reference_section_type: RESULTS
- term:
    id: GO:0036041
    label: long-chain fatty acid binding
  evidence_type: IDA
  original_reference_id: PMID:25554789
  review:
    summary: >-
      Folick et al. (PMID:25554789) demonstrated LBP-8 binding to long-chain fatty
      acids
      (arachidonic acid, omega-3 arachidonic acid, DGLA) and OEA using fluorescence-based
      binding
      assays. Tillman et al. (PMID:31292465) confirmed and extended this with LC/MS
      showing binding
      to a diverse range of long-chain fatty acids including oleic acid, arachidonic
      acid, linoleic
      acid, palmitic acid, and stearic acid.
    action: ACCEPT
    reason: >-
      Long-chain fatty acid binding is directly demonstrated by IDA evidence. Fluorescence-based
      binding assays (PMID:25554789) and mass spectrometry co-purification (PMID:31292465)
      both confirm LBP-8 binds diverse long-chain fatty acids. This is a core molecular
      function
      and the term is at the right level of specificity.
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        we focused our analysis on three C20 fatty acids—arachidonic acid (AA), ω-3
        arachidonic
        acid (ω-3 AA), and dihomo-γ-linolenic acid (DGLA)—and oleoylethanolamide (OEA)
        ...
        all four lipids bound to LBP-8
    - reference_id: PMID:31292465
      supporting_text: >-
        LBP-8 does not bind to one fatty acid selectively but is capable of binding
        many
        fatty acids. However, LBP-8 does have a preference for unsaturated fatty acids
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        a preference for **monounsaturated fatty acyls**
      reference_section_type: RESULTS
- term:
    id: GO:0006869
    label: lipid transport
  evidence_type: TAS
  original_reference_id: PMID:10693745
  review:
    summary: >-
      Plenefisch et al. (PMID:10693745) identified LBP-8 as one of nine C. elegans
      FABP homologs.
      The paper primarily focused on LBP-1, LBP-2, and LBP-3 (the secreted FABPs),
      and did not
      directly study LBP-8 function. The TAS evidence for lipid transport is based
      on homology
      to other FABPs. While the annotation is correct (LBP-8 does transport lipids),
      the evidence
      is weak for this specific gene. However, the annotation itself is valid given
      later
      experimental confirmation.
    action: ACCEPT
    reason: >-
      Lipid transport is a correct annotation for LBP-8, now thoroughly validated
      by later
      experimental work (PMID:25554789, PMID:31292465). While the original TAS reference
      (PMID:10693745) mainly studied other C. elegans FABPs (LBP-1, LBP-2, LBP-3),
      the
      general assignment of lipid transport to the FABP family was appropriate. More
      specific
      annotations (long-chain fatty acid transport) are also present with stronger
      evidence.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:10693745
      supporting_text: >-
        at least eight potential homologues of As-p18 have been identified in the
        Caenorhabditis elegans genome
    - reference_id: PMID:25554789
      supporting_text: >-
        LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals
        to the nucleus
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8’s primary molecular function is expected to be ligand binding and intracellular transport/targeting of hydrophobic metabolites
      reference_section_type: RESULTS
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: TAS
  original_reference_id: PMID:10693745
  review:
    summary: >-
      Plenefisch et al. (PMID:10693745) identified LBP-8 as a FABP homolog in C. elegans.
      The TAS
      annotation for lipid binding is based on homology to fatty acid binding proteins.
      While the
      original paper mainly studied LBP-1/2/3, the annotation is correct and validated
      by later work.
      More specific annotations (fatty acid binding, long-chain fatty acid binding,
      oleic acid
      binding) are also present.
    action: ACCEPT
    reason: >-
      Lipid binding is correct for LBP-8, validated by extensive experimental evidence
      (PMID:25554789, PMID:31292465). The TAS evidence from PMID:10693745 was based
      on
      homology to known FABPs, which proved accurate. The annotation is broader than
      the
      more specific IDA/IBA annotations but acceptable.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        LBP-8 binds long-chain fatty acids and fatty-acid derivatives.
      reference_section_type: RESULTS
- term:
    id: GO:0032365
    label: intracellular lipid transport
  evidence_type: IDA
  original_reference_id: PMID:25554789
  review:
    summary: >-
      LBP-8 is an intracellular lipid chaperone that shuttles fatty acid signals from
      lysosomes
      to the nucleus. Folick et al. (PMID:25554789) demonstrated lysosome-to-nucleus
      translocation
      of LBP-8 carrying lipid signals including OEA. This intracellular lipid transport
      function
      is the core biological process of LBP-8.
    action: NEW
    reason: >-
      GO:0032365 (intracellular lipid transport) is more precise than GO:0006869 (lipid
      transport)
      for describing LBP-8 function, as it specifically captures the intracellular
      nature of the
      lipid shuttling. LBP-8 transports lipids from lysosomes to nucleus within the
      cell. This term
      is not present in the current annotation set but is well-supported by experimental
      evidence.
    additional_reference_ids:
    - file:worm/lbp-8/lbp-8-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:25554789
      supporting_text: >-
        LBP-8 may function as a lysosomal lipid chaperone transducing lipid signals
        to the nucleus
    - reference_id: PMID:31292465
      supporting_text: >-
        certain human FABPs have been shown to shuttle nuclear receptor ligands into
        the
        nucleus to regulate nuclear receptor transcription
    - reference_id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
      supporting_text: |-
        functions as a **lysosome-to-nucleus lipid chaperone**
      reference_section_type: RESULTS
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings:
  - statement: LBP-8 contains the FABP domain (IPR000463), which maps to lipid binding
      (GO:0008289)
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: >-
      Phylogenetic inference supports LBP-8 annotations for nucleus, cytosol, fatty
      acid binding,
      and fatty acid transport, consistent with the broader FABP family
- id: GO_REF:0000044
  title: >-
    Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings:
  - statement: >-
      UniProt subcellular location mapping correctly assigns LBP-8 to nucleus and
      lysosome,
      consistent with direct experimental evidence from PMID:25554789
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings:
  - statement: ARBA correctly predicts fatty acid binding for LBP-8 based on sequence
      features
- id: PMID:10693745
  title: 'Secretion of a novel class of iFABPs in nematodes: coordinate use of the
    Ascaris/Caenorhabditis model systems.'
  findings:
  - statement: >-
      LBP-8 identified as one of at least eight C. elegans homologs of the Ascaris
      fatty acid binding
      protein As-p18. The paper focused on the secreted FABPs (LBP-1, LBP-2, LBP-3)
      but established
      the FABP family membership of LBP-8.
    supporting_text: >-
      at least eight potential homologues of As-p18 have been identified in the
      Caenorhabditis elegans genome
- id: PMID:25554789
  title: Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis
    elegans.
  findings:
  - statement: >-
      LBP-8 is a lysosomal lipid chaperone that translocates from lysosomes to the
      nucleus upon
      LIPL-4 overexpression. LBP-8 overexpression extends lifespan by 30%. LBP-8 is
      required for
      LIPL-4-mediated longevity. LBP-8 binds OEA with 3-fold higher affinity than
      C20 fatty acids.
      LBP-8 nuclear localization requires its NLS. LBP-8 activates NHR-49/NHR-80-dependent
      transcription of acs-2. LBP-8 is exclusively expressed in the intestine.
    supporting_text: >-
      In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered
      nuclear
      translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity
      by
      activating the nuclear hormone receptors NHR-49 and NHR-80
- id: PMID:31292465
  title: Structural characterization of life-extending Caenorhabditis elegans Lipid
    Binding Protein 8.
  findings:
  - statement: >-
      Crystal structure of LBP-8 solved at 1.3 angstrom resolution (PDB 6C1Z). LBP-8
      is a monomer
      with a typical lipocalin fold. A structurally conserved NLS (K24, R33, K34)
      was identified in
      the portal region. Mass spectrometry identified a broad range of fatty acids
      co-purifying with
      LBP-8, with preference for monounsaturated fatty acids. Oleic acid was the most
      abundant bound
      fatty acid. Both oleic acid and OEA bind with high affinity (similar Ki values).
      Oleic acid
      destabilizes LBP-8, decreasing Tm by approximately 4 degrees C, while OEA has
      no effect on stability.
    supporting_text: >-
      we determined the first 1.3 Å high-resolution structure of this life-extending
      protein LBP-8, which allowed us to identify a structurally conserved nuclear
      localization signal and amino acids involved in lipid binding
- id: PMID:30713071
  title: Lysosomal Signaling Promotes Longevity by Adjusting Mitochondrial Activity.
  full_text_unavailable: true
  findings:
  - statement: >-
      Ramachandran et al. showed that the LIPL-4/LBP-8 lysosomal signaling pathway
      promotes
      longevity by adjusting mitochondrial activity, specifically through activation
      of
      mitochondrial beta-oxidation. This extends the understanding of LBP-8's downstream
      effects beyond nuclear receptor activation.
- id: file:worm/lbp-8/lbp-8-deep-research-falcon.md
  title: Falcon (Edison Scientific) deep research report on C. elegans lbp-8 (O02324)
  findings:
  - statement: |-
      LBP-8 is best annotated as a non-enzymatic intracellular lipid chaperone
      (FABP/iLBP, calycin/lipocalin-like fold) that binds hydrophobic ligands and
      delivers lysosome-derived lipid signals to nuclear transcriptional regulators
      rather than catalyzing a reaction.
    supporting_text: |-
      LBP-8 is a **non-enzymatic intracellular lipid chaperone** that transfers lysosome-derived lipid signals to the nucleus. It does **not catalyze a reaction**; instead, it binds hydrophobic ligands and facilitates their delivery to transcriptional regulators.
    reference_section_type: RESULTS
  - statement: |-
      LBP-8 binds long-chain fatty acids and fatty-acid derivatives, including OEA,
      oleic acid, arachidonic acid, omega-3 AA, and DGLA, with OEA binding ~3-fold
      more tightly than the tested fatty acids and an overall preference for
      monounsaturated fatty acyls.
    supporting_text: |-
      Reported ligands include **oleoylethanolamide (OEA)**, **oleic acid**, **arachidonic acid (AA)**, **ω-3 AA**, and **DGLA**; competition assays showed **OEA binds with ~3-fold higher affinity** than the tested fatty acids.
    reference_section_type: RESULTS
  - statement: |-
      LBP-8 localizes predominantly to intestinal lysosomes (co-localizing with the
      lysosomal marker LMP-1) and also appears in nuclear and cytosolic fractions,
      with lipl-4 overexpression enhancing the nuclear fraction; lbp-8 expression is
      reported as exclusive to the intestine.
    supporting_text: |-
      LBP-8 is predominantly **lysosomal in intestinal cells**, co-localizing with lysosomal marker **LMP-1**, and also appears in nuclear and cytosolic fractions; **lipl-4** overexpression enhances the nuclear fraction.
    reference_section_type: RESULTS
  - statement: |-
      A conserved structural nuclear localization signal formed by basic residues
      K24/R33/K34 is required for nuclear translocation; deletion or mutation of this
      region abolishes nuclear import.
    supporting_text: |-
      conserved, structural **nuclear localization signal (NLS)** formed by basic residues (K24/R33/K34). Deletion/mutation of this region abolishes nuclear translocation.
    reference_section_type: RESULTS
  - statement: |-
      In the lysosome-to-nucleus lipid signaling pathway LBP-8 carries OEA to nuclear
      hormone receptors; NHR-80 binds OEA directly (Kd = 7.841 uM) whereas no OEA
      binding was detected for NHR-49, consistent with NHR-49 acting as a partner
      rather than the direct OEA-binding receptor.
    supporting_text: |-
      NHR-80 binds OEA directly with **Kd = 7.841 µM** (intrinsic fluorescence assay), whereas no OEA binding was detected for NHR-49 in that study, consistent with NHR-49 acting in a receptor complex rather than as the direct OEA-binding receptor.
    reference_section_type: RESULTS
  - statement: |-
      The ligand cavity is lined by hydrophobic residues plus polar residues including
      the conserved R132, implicated in fatty-acid head-group recognition.
    supporting_text: |-
      lined by hydrophobic residues plus polar residues including conserved **R132**, implicated in head-group interactions.
    reference_section_type: RESULTS
  - statement: |-
      A 2021 proteomic-genetic study identified the nuclear factor RPC-2 as required
      both for LBP-8-mediated longevity and for robust nuclear localization of LBP-8,
      indicating that nuclear import (not export) drives the longevity effect.
    supporting_text: |-
      nuclear factor **RPC-2**, which was also necessary for robust nuclear localization of LBP-8; nuclear **import**, rather than export, was required for the longevity effect.
    reference_section_type: RESULTS
  - statement: |-
      Within a broader inter-tissue lysosomal lipid-signaling network, LBP-3 and LBP-8
      can have additive effects on lifespan, with nhr-49 required downstream of
      intestine-derived lysosomal lipid signaling.
    supporting_text: |-
      **LBP-3** and **LBP-8** can have additive effects on lifespan; **nhr-49** is required downstream of intestine-derived lysosomal lipid signaling to neuropeptide pathways.
    reference_section_type: RESULTS
core_functions:
- description: >-
    LBP-8 binds long-chain fatty acids and oleoylethanolamide (OEA) with high
    affinity and transfers them between intracellular membranes and acceptor
    proteins. Oleic acid and OEA are the preferred ligands. The conserved R132
    residue coordinates fatty acid head groups in the binding cavity.
  molecular_function:
    id: GO:0120013
    label: lipid transfer activity
  directly_involved_in:
  - id: GO:0032365
    label: intracellular lipid transport
  - id: GO:0015909
    label: long-chain fatty acid transport
  locations:
  - id: GO:0005764
    label: lysosome
  - id: GO:0005829
    label: cytosol
  substrates:
  - id: CHEBI:16196
    label: oleic acid
  - id: CHEBI:73497
    label: oleoylethanolamide
  supported_by:
  - reference_id: PMID:31292465
    supporting_text: >-
      we described the range of fatty acids LBP-8 is capable of binding and
      show that it binds to life-extending ligands in worms such as oleic
      acid and oleoylethanolamide with high affinity
  - reference_id: PMID:25554789
    supporting_text: >-
      all four lipids bound to LBP-8, and the binding affinity of OEA for
      LBP-8 was 3 times higher than that of the fatty acids
- description: >-
    LBP-8 shuttles OEA and oleic acid from lysosomes to the nucleus via its
    structurally conserved NLS (K24, R33, K34), delivering these lipid ligands
    to the nuclear hormone receptors NHR-49 and NHR-80. This activates
    transcription of beta-oxidation genes (acs-2) and promotes longevity.
    Nuclear translocation is enhanced by LIPL-4-generated lysosomal lipid
    signals and is required for lifespan extension.
  molecular_function:
    id: GO:0120013
    label: lipid transfer activity
  directly_involved_in:
  - id: GO:0032365
    label: intracellular lipid transport
  - id: GO:0008340
    label: determination of adult lifespan
  locations:
  - id: GO:0005634
    label: nucleus
  anatomical_locations:
  - id: UBERON:0000160
    label: intestine
  supported_by:
  - reference_id: PMID:25554789
    supporting_text: >-
      the lysosomal acid lipase LIPL-4 triggered nuclear translocalization
      of a lysosomal lipid chaperone LBP-8, which promoted longevity by
      activating the nuclear hormone receptors NHR-49 and NHR-80
  - reference_id: PMID:31292465
    supporting_text: >-
      certain human FABPs have been shown to shuttle nuclear receptor
      ligands into the nucleus to regulate nuclear receptor transcription
  - reference_id: PMID:30713071
    supporting_text: >-
      Lysosomal Signaling Promotes Longevity by Adjusting Mitochondrial Activity

lbp-8

Gene Description

Existing Annotations Review

Core Functions

LBP-8 binds long-chain fatty acids and oleoylethanolamide (OEA) with high affinity and transfers them between intracellular membranes and acceptor proteins. Oleic acid and OEA are the preferred ligands. The conserved R132 residue coordinates fatty acid head groups in the binding cavity.

References

Deep Research

Falcon

Research report: Caenorhabditis elegans lbp-8 (UniProt O02324; WormBase locus T22G5.6)—functional annotation

1) Gene/protein identity verification (mandatory)

2) Key concepts and definitions (current understanding)

2.1 What are FABPs/iLBPs/calycins?

2.2 Implication for LBP-8 biochemical function

3) Molecular function: ligands (“substrates”), binding, and structural determinants

3.1 Ligand classes bound by LBP-8

3.2 Structural basis for binding and trafficking

4) Biological role and pathways: lysosome-to-nucleus lipid signaling and longevity

4.1 Core pathway model

4.2 Quantitative phenotypes and transcriptional outputs

4.3 Receptor/ligand specificity within the pathway

5) Subcellular and tissue localization (where LBP-8 acts)

5.1 Tissue restriction

5.2 Organelle and nuclear localization

6) Recent developments (prioritizing 2023–2024) and current expert analysis

6.1 2023: NHR-49 as an aging/stress hub contextualizes lbp-8

6.2 2024: FABPs as sensors/conveyors/modulators—supporting mechanistic interpretation

6.3 Note on 2023–2024 lbp-8-specific primary literature

7) Current applications and real-world implementations

8) Evidence summary table

9) Concise functional annotation (recommended)

Artifacts

Citations

📚 Additional Documentation

Notes

lbp-8 Research Notes

Gene Overview

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

Structural Features

Lipid Binding

Subcellular Localization

Longevity Function

Regulation

Early Characterization

📄 View Raw YAML