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)

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

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."