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.
| 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 Γ
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)**, **Ο-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 acidsβarachidonic acid (AA), Ο-3 arachidonic acid (Ο-3 AA), and dihomo-Ξ³-linolenic acid (DGLA)βand 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-8βs 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** |
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