Gene Ontology annotation through association of InterPro records with GO terms

InterPro domains IPR006693 (AB hydrolase lipase) and IPR025483 (eukaryotic lipase) map to lipid metabolic process and hydrolase activity acting on ester bonds, respectively.

Annotation inferences using phylogenetic trees

Phylogenetic analysis by PANTHER/GO_Central supports lipase activity and lipid metabolic process annotations for LIPL-4 based on conservation across eukaryotic lipase family members including yeast, fly, and mammalian orthologs.

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 annotation of lysosome lumen is mapped to GO:0043202. This is based on experimental evidence from PMID:25554789.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Rhea reaction mapping from EC 3.1.1.3 supports triacylglycerol lipase activity annotation.

PMID:21906946

Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans.

LIPL-4 has triacylglycerol lipase activity. In germline-less (glp-1) animals, lipl-4 is required for increased lipase activity and for autophagy induction. Reciprocally, autophagy is required to maintain high LIPL-4-dependent lipase activity. LIPL-4 overexpression induces autophagy and extends lifespan, and autophagy is required for this lifespan extension. TOR inhibition induces lipl-4 expression.

"autophagy is required to maintain high lipase activity in germline-deficient animals. Reciprocally, lipl-4 is required for autophagy induction."

PMID:23392608

ω-6 Polyunsaturated fatty acids extend life span through the activation of autophagy.

Upon fasting, LIPL-4 induction leads to enrichment of omega-6 PUFAs (AA, DGLA) that serve as metabolic signals activating autophagy. Supplementation with these omega-6 PUFAs extends C. elegans lifespan and activates autophagy in both worms and human cells. LIPL-4 overexpression also transcriptionally activates nutrient-responsive genes including fatty acid-binding proteins lbp-3 and lbp-5.

"LIPL-4 overexpression is sufficient to not only enrich omega-6 PUFAs and activate autophagy, but also transcriptionally activate nutrient-responsive genes"
LIPL-4 does not localize to sites of active autophagy, suggesting it is not directly involved in lipophagy but rather produces signaling lipids that activate autophagy.

"LIPL-4 does not localize to the sites of active autophagy"

PMID:25554789

Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans.

LIPL-4 localizes to intestinal lysosomes (FLAG-tagged protein). Lipid hydrolysis activity is reduced in lipl-4 loss-of-function mutants at pH 4.5 but not pH 7.4, confirming acid lipase activity. Constitutive lipl-4 expression extends lifespan by 55%, requiring the signal peptide for lysosomal targeting. Metabolomic profiling identified increased abundance of C20 fatty acids (AA, omega-3 AA, DGLA) and OEA in lipl-4 Tg animals. OEA binds LBP-8 and directly activates NHR-80, promoting longevity gene transcription through a lysosome-to-nucleus signaling pathway.

"FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig. 1, B–D and fig. S2)."
The signal peptide is required for lysosomal localization and the longevity effect. LIPL-4 without signal peptide is not targeted to lysosomes and causes little lifespan extension.

"Constitutive expression of LIPL-4 without the signal peptide (lipl-4 Tg no SP), which was not targeted to the lysosome, caused little extension of lifespan (fig. S4 and table S1), suggesting that the lysosomal activity of LIPL-4 is essential for its longevity effect."

file:worm/lipl-4/lipl-4-deep-research-falcon.md

Falcon deep research report on lipl-4 (C. elegans)

LIPL-4 is a lysosomal acid lipase-like AB-hydrolase expressed prominently in the intestine and localized to lysosomes via an N-terminal signal peptide, where it shows acid pH-dependent triglyceride lipase activity that drives lysosome-derived lipid signaling promoting longevity.

"**lipl-4** encodes **LIPL-4**, a **lysosomal acid lipase-like** enzyme expressed prominently in the **intestine** (major fat storage tissue) and localized to **lysosomes** via an N-terminal signal peptide. Experimentally, LIPL-4 shows **acid pH-dependent triglyceride lipase activity** and drives **lysosome-derived lipid signaling** that promotes longevity"
Lysosomal acid lipases including LIPL-4 release free fatty acids from triacylglycerols and cholesteryl esters in intestinal lysosomes.

"Savini et al. describe lysosomal acid lipases (including LIPL-4) as releasing **free fatty acids** from **triacylglycerols (TAGs)** and **cholesteryl esters (CEs)**, situating LIPL-4 within TAG/CE lipolysis and FFA generation in intestinal lysosomes."
FLAG-tagged LIPL-4 co-localizes with the lysosomal marker LMP-1 in intestinal cells, and its signal peptide is required for lysosomal targeting and for full downstream signaling and longevity.

"FLAG-tagged LIPL-4 **co-localizes with the lysosomal marker LMP-1** in **intestinal cells**, indicating LIPL-4 is a lysosomal protein in vivo."
One pro-longevity arm of LIPL-4 signaling acts via the lipid chaperone LBP-8 and nuclear receptors NHR-49 and NHR-80, with OEA binding LBP-8 with about 3-fold higher affinity than other LIPL-4-associated lipids.

"LIPL-4-driven longevity requires **LBP-8** and the nuclear receptors **NHR-49** and **NHR-80**, consistent with a lysosome-generated lipid ligand being chaperoned to the nucleus to alter transcription."
The LIPL-4/LBP-8 axis links to mitochondrial physiology, increasing beta-oxidation, raising mtROS, and activating JUN-1-dependent stress-response transcription that improves oxidative stress tolerance and promotes longevity.

"LIPL-4 signaling also increases mitochondrial β-oxidation and mtROS/JUN-1 responses."
A second, intestine-to-neuron arm uses the secreted lipid chaperone LBP-3 binding specific PUFAs (notably DGLA) and acting through neuronal NHR-49 and the neuropeptide NLP-11 to promote longevity.

"A secreted lipid chaperone, **LBP-3**, binds specific PUFAs and is required for LIPL-4-induced neuronal changes and longevity."
Intestinal LIPL-4 signaling induces neuronal neuropeptide signaling dependent on neuronal NHR-49 and the neuropeptide NLP-11, with DGLA highlighted as a key PUFA mediator.

"Intestinal LIPL-4 signaling induces neuronal **neuropeptide signaling**; functional experiments show dependence on neuronal **NHR-49** and neuropeptide **NLP-11**."
2024 lysosome immunopurification proteomics shows lipl-4 transgenic worms have extensive lysosome proteome remodeling (449 lysosome-enriched proteins, only 39% overlap with WT) and perinuclear lysosome clustering in intestinal cells.

"**449 lysosome-enriched proteins** identified in lipl-4 Tg, with only **39% overlap** vs WT lysosome-enriched proteins; **61%** of proteins enriched on lipl-4 Tg lysosomes were absent from WT lysosomes."
lipl-4 transgenic longevity depends on nuclear import machinery (npp-6 nucleoporin, ima-3 importin-alpha) and lysosome-associated AMPK; impairing AMPK reduces the lipl-4 Tg lifespan extension from 72% to 48%.

"reduces lipl-4 Tg extension from **72% to 48%**."