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 Ų surface area, 1170 ų 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