C. elegans Lysosome-to-Nucleus Lipid Signaling (OEA Pathway)
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
- lipl-4 - Lysosomal acid lipase; generates OEA and omega-6 PUFAs from TAG hydrolysis
Signal Transport
- lbp-8 - Fatty acid-binding protein (FABP); shuttles OEA from lysosome to nucleus via NLS
Nuclear Reception
- nhr-80 - Nuclear hormone receptor (HNF4 homolog); direct OEA receptor (Kd ~7.8 uM)
- nhr-49 - Nuclear hormone receptor (HNF4 homolog); heterodimerization partner; does NOT bind OEA directly
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
- nhr-49 - Essential heterodimerization partner of NHR-80. Regulates both desaturation (with NHR-80) and beta-oxidation (with NHR-66). Does NOT bind OEA directly but is required for pathway output. More pleiotropic than NHR-80 (also regulates sphingolipid metabolism). nhr-49 mutants have dramatic lifespan reduction (~41%) and fat storage increase.
Lower Priority (Downstream/Contextual)
- fat-5, fat-6, fat-7 - Delta-9 desaturase targets of NHR-80/NHR-49 transcriptional regulation
- acs-2 - Acyl-CoA synthetase for beta-oxidation; >15-fold induced by LIPL-4 Tg
- hlh-30 - TFEB homolog that regulates lipl-4 expression (already reviewed in this repo)
- daf-16 - FOXO; regulates lipl-4 induction in germline-less context (already reviewed)
- glp-1 - Notch receptor; germline proliferation; glp-1 mutants are the canonical longevity context
Key Publications
- PMID:25554789 - Folick et al. 2015 - Discovery of OEA as lysosomal lipid signal; LBP-8 as chaperone; NHR-80 as OEA receptor
- PMID:31292465 - Hughes et al. 2019 - LBP-8 crystal structure; ligand binding characterization
- PMID:21906946 - Lapierre et al. 2011 - LIPL-4 and autophagy coordinate longevity
- PMID:23392608 - O'Rourke & Ruvkun 2013 - Omega-6 PUFAs from LIPL-4 activate autophagy
- PMID:16839188 - Brock et al. 2006 - NHR-80 regulates delta-9 desaturases
- PMID:22511885 - Pathare et al. 2012 - NHR-49/NHR-80 coordinate lipid metabolism
- PMID:21423649 - Goudeau et al. 2011 - NHR-80 links germline loss to longevity via fat-6