C. elegans Lysosome-to-Nucleus Lipid Signaling (OEA Pathway)

IN_PROGRESS BIOLOGY_DOMAIN

Species: worm

Genes: lipl-4 lbp-8 nhr-80 nhr-49

C. elegans Lysosome-to-Nucleus Lipid Signaling (OEA Pathway)

Bottom line: in C. elegans, the lysosomal lipase LIPL-4 releases
oleoylethanolamide (OEA), the lipid chaperone LBP-8 carries it to the
nucleus, and the nuclear receptor NHR-80, with its partner NHR-49, switches
on fatty acid desaturase and beta-oxidation genes to extend lifespan
(PMID:25554789). We reviewed every existing GO annotation on these four
genes. All four reviews are done: 74 rows: 60 ACCEPT, 3 KEEP_AS_NON_CORE, 1
MARK_AS_OVER_ANNOTATED, 6 MODIFY and 4 NEW proposals. The corrections make the mechanism explicit: LBP-8's
long-chain fatty acid transmembrane transporter activity becomes lipid
transfer activity, NHR-80's generic DNA-binding transcription factor row
becomes ligand-modulated transcription factor activity, and NHR-49's four
protein binding rows become DNA-binding transcription factor binding.
The downstream targets (fat-5, fat-6, fat-7, acs-2) and glp-1 are not yet
reviewed; nhr-49, still listed under "Missing Genes" below, is now done.

We did this because the pathway is short and well characterised, with a
direct ligand-receptor measurement for OEA and NHR-80, which makes it a good
test of whether GO terms can express a lysosome-to-nucleus lipid signal.

Overview

The LIPL-4/LBP-8/NHR-80 pathway is a lysosome-to-nucleus retrograde lipid signaling axis that promotes longevity in C. elegans. The lysosomal lipase LIPL-4 generates oleoylethanolamide (OEA) and omega-6 PUFAs, which are chaperoned by the fatty acid-binding protein LBP-8 to the nucleus, where OEA directly binds and activates the nuclear receptor NHR-80. NHR-80 heterodimerizes with NHR-49 to drive transcription of fatty acid desaturases (fat-5/6/7) and beta-oxidation genes (acs-2). This pathway is required for germline-mediated (glp-1) longevity and is separable from insulin/IGF (daf-2) and dietary restriction longevity pathways.

Key reference: Folick et al. 2015 (PMID:25554789)

Model Species

Primary: Caenorhabditis elegans (worm)
- UniProt species code: CAEEL

Core Pathway Architecture

Lysosome                        Cytoplasm                   Nucleus
┌──────────────┐               ┌──────────────┐          ┌──────────────────────┐
│  LIPL-4      │  OEA/PUFAs   │              │          │  NHR-80 + NHR-49     │
│  (acid lipase)├──────────────►  LBP-8 ──────────────►  │  (HNF4 homologs)     │
│              │               │  (FABP)      │          │        │              │
│  TAG → OEA   │               │              │          │  fat-5/6/7, acs-2    │
└──────────────┘               └──────────────┘          └──────────────────────┘

Signal Generation

Signal Transport

Nuclear Reception

Gene Review Status

Gene UniProt Status Annotations Core Functions Notes
lipl-4 Q94252 IN_PROGRESS 14 reviewed Yes Lysosomal acid lipase, signal generator
lbp-8 O02324 IN_PROGRESS 17 reviewed Yes Lipid chaperone, lysosome-to-nucleus shuttle
nhr-80 Q8ITW8 IN_PROGRESS 16 reviewed Yes OEA receptor, desaturase regulator
nhr-49 O45666 IN_PROGRESS 28 reviewed Yes (3) Orphan NHR; fatty acid metabolism, longevity, hypoxia

Missing Genes

High Priority

Lower Priority (Downstream/Contextual)

Key Publications

Cross-References to Other Projects

Slides