LIPL-4 is a lysosomal acid lipase in C. elegans with triacylglycerol lipase activity (EC 3.1.1.3) that functions as a key signaling enzyme in a lysosome-to-nucleus retrograde lipid signaling pathway promoting longevity. LIPL-4 localizes to the lysosomal lumen via a signal peptide and is optimally active at acidic pH. Upon fasting or germline loss, LIPL-4 is upregulated in the intestine and produces lipid signaling molecules including oleoylethanolamide (OEA) and omega-6 polyunsaturated fatty acids (PUFAs such as arachidonic acid and DGLA). OEA is carried by the lipid chaperone LBP-8 from the lysosome to the nucleus, where it directly binds and activates the nuclear hormone receptor NHR-80 (with NHR-49 as a cofactor), promoting transcription of longevity and beta-oxidation genes. Omega-6 PUFAs produced by LIPL-4 activate autophagy, contributing to lifespan extension. Constitutive overexpression of LIPL-4 extends lifespan by approximately 55%, an effect that requires lysosomal localization (signal peptide dependent). LIPL-4 expression is regulated by the transcription factors MXL-3 and HLH-30 in response to nutrient availability, and is induced by TOR inhibition. The protein belongs to the AB hydrolase superfamily lipase family and is homologous to human lysosomal acid lipase LIPA. Two isoforms exist (a and b), with isoform b lacking the N-terminal 157 residues including the signal peptide.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006629 lipid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of lipid metabolic process based on phylogenetic inference across multiple orthologs including yeast, fly, and mammalian lipases. LIPL-4 is clearly involved in lipid metabolism as a lysosomal triacylglycerol lipase that hydrolyzes triglycerides and produces fatty acid signaling molecules (PMID:21906946, PMID:25554789). Reason: LIPL-4 is unambiguously involved in lipid metabolic process. While more specific terms exist (triglyceride catabolic process, long-chain fatty acid biosynthetic process), this broader IBA annotation is appropriate as a phylogenetically supported annotation and is not incorrect. Multiple publications confirm lipase activity and lipid metabolism roles (PMID:21906946, PMID:23392608, PMID:25554789). Supporting Evidence: PMID:21906946 Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4 PMID:25554789 We analyzed a C. elegans longevity-promoting lipase, LIPL-4, which has sequence and functional similarities to human LIPA file:worm/lipl-4/lipl-4-deep-research-falcon.md 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. |
| GO:0016298 lipase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of lipase activity based on phylogenetic inference. LIPL-4 has experimentally demonstrated lipase activity, specifically triacylglycerol lipase activity (PMID:21906946). Lipid hydrolysis activity was confirmed at pH 4.5 in worm lysates (PMID:25554789). Reason: Lipase activity is well supported by multiple lines of evidence. While the more specific term triacylglycerol lipase activity (GO:0004806) is also annotated, this broader IBA annotation is appropriate as a phylogenetically supported characterization. The IBA annotation represents the consensus across the lipase family tree and is not incorrect. Supporting Evidence: PMID:25554789 Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants at pH 4.5 but not at pH 7.4 PMID:21906946 autophagy is required to maintain high lipase activity in germline-deficient animals file:worm/lipl-4/lipl-4-deep-research-falcon.md mutants have **reduced hydrolysis at pH 4.5 but not pH 7.4**, supporting **acid pH-dependent triglyceride lipase activity** consistent with lysosomal function. |
| GO:0004806 triacylglycerol lipase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation of triacylglycerol lipase activity based on Rhea/EC mapping (EC:3.1.1.3). This is consistent with the UniProt catalytic activity annotation and the experimentally determined IMP annotation from PMID:21906946. Reason: This IEA annotation is correct and consistent with the IMP annotation from PMID:21906946. UniProt assigns EC 3.1.1.3 based on experimental evidence from multiple publications. The triacylglycerol lipase activity is a core molecular function of LIPL-4. Supporting Evidence: PMID:21906946 Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4 file:worm/lipl-4/lipl-4-deep-research-falcon.md The direct biochemical assay supports activity against a **triacylglycerol** substrate (triolein). |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation of lipid metabolic process based on InterPro domain mapping (IPR006693, AB hydrolase lipase domain). This is consistent with the IBA annotation for the same term and with experimental evidence. Reason: This IEA annotation is correct and redundant with the IBA annotation. The InterPro domain-based inference is sound given the established lipase function of LIPL-4. Duplicates with different evidence codes are acceptable. Supporting Evidence: PMID:21906946 Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4 |
| GO:0016788 hydrolase activity, acting on ester bonds | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation of hydrolase activity acting on ester bonds, based on InterPro domain mapping (IPR025483, eukaryotic lipase). LIPL-4 has a catalytic triad (Ser177, Asp352, His384) characteristic of the AB hydrolase superfamily and hydrolyzes ester bonds in triacylglycerols. Reason: This is a correct but general parent term of the more specific triacylglycerol lipase activity. The IEA mapping from the eukaryotic lipase InterPro domain is appropriate. While broader than other MF annotations, it is not incorrect and reflects the domain-level inference. Supporting Evidence: PMID:25554789 Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants at pH 4.5 but not at pH 7.4 |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation of lysosomal lumen localization based on UniProt subcellular location vocabulary mapping. UniProt annotates LIPL-4 to "Lysosome lumen" based on experimental evidence from PMID:25554789 showing FLAG-tagged LIPL-4 co-localizing with lysosomal markers in intestinal cells. Reason: Lysosomal lumen localization is strongly supported by experimental evidence. LIPL-4 has a signal peptide (residues 1-27) required for lysosomal targeting, and its optimal activity at acidic pH is consistent with lysosomal lumen function. The signal peptide is required for both lysosomal localization and the longevity effect (PMID:25554789). This IEA correctly reflects the experimentally validated UniProt subcellular location annotation. Supporting Evidence: PMID:25554789 FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig PMID:25554789 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 A **signal peptide** required for lysosomal targeting is also required for full downstream signaling and longevity phenotypes, consistent with LIPL-4 acting from the lysosomal lumen/lysosomal compartment. |
| GO:0005764 lysosome | IDA PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C... | ACCEPT | Summary: IDA annotation of lysosome localization based on direct observation of FLAG-tagged LIPL-4 protein co-localizing with lysosomal markers in intestinal cells (PMID:25554789). The signal peptide is required for lysosomal targeting and the longevity phenotype. Reason: Lysosomal localization is a core aspect of LIPL-4 function, experimentally demonstrated by fluorescence microscopy of tagged protein. The requirement of the signal peptide for both lysosomal localization and longevity function establishes that lysosomal localization is functionally essential (PMID:25554789). Supporting Evidence: PMID:25554789 FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig PMID:25554789 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 FLAG-tagged LIPL-4 **co-localizes with the lysosomal marker LMP-1** in **intestinal cells**, indicating LIPL-4 is a lysosomal protein in vivo. |
| GO:0042759 long-chain fatty acid biosynthetic process | IMP PMID:25554789 Aging. Lysosomal signaling molecules regulate longevity in C... | ACCEPT | Summary: IMP annotation of long-chain fatty acid biosynthetic process. PMID:25554789 identified via high-throughput metabolomic profiling that lipl-4 overexpression increases abundance of several long-chain fatty acids including arachidonic acid (AA), omega-3 AA, DGLA (C20 fatty acids), and oleoylethanolamide (OEA). PMID:23392608 showed that lipl-4 induction leads to enrichment of omega-6 PUFAs. Reason: The metabolomic data from PMID:25554789 clearly show that LIPL-4 overexpression leads to increased abundance of long-chain fatty acids. While LIPL-4 is primarily a lipase (hydrolase), its activity leads to the production/accumulation of long-chain fatty acid species and their derivatives. The term captures the biological outcome of LIPL-4 activity at the organismal level, even though the molecular mechanism is hydrolytic release of fatty acids from triacylglycerols rather than de novo biosynthesis. Supporting Evidence: PMID:25554789 we focused our analysis on three C20 fatty acidsβarachidonic acid (AA), omega-3 arachidonic acid (omega-3 AA), and dihomo-gamma-linolenic acid (DGLA)βand oleoylethanolamide (OEA), an N-acylethanolamine fatty acid derivative PMID:23392608 LIPL-4 overexpression is sufficient to not only enrich omega-6 PUFAs and activate autophagy, but also transcriptionally activate nutrient-responsive genes file:worm/lipl-4/lipl-4-deep-research-falcon.md LIPL-4 overexpression is associated with increases in several lipid species, including **oleoylethanolamide (OEA)** and PUFAs |
| GO:0005737 cytoplasm | IDA PMID:23392608 Ο-6 Polyunsaturated fatty acids extend life span through the... | KEEP AS NON CORE | Summary: IDA annotation of cytoplasm localization from CACAO curation of PMID:23392608. O'Rourke et al. (2013) studied LIPL-4 localization but noted that LIPL-4 does not localize to sites of active autophagy. The primary experimentally validated localization is lysosomal (PMID:25554789), which is a more specific compartment within the cytoplasm. Reason: While cytoplasm is technically not incorrect (lysosomes are within the cytoplasm), the more specific and functionally relevant localization is lysosomal lumen (GO:0043202) as demonstrated by PMID:25554789. The CACAO annotation predates the definitive lysosomal localization study. However, it is not wrong per se, so keeping as non-core rather than removing. The lysosome annotation (GO:0005764) is the core CC annotation. Supporting Evidence: PMID:23392608 LIPL-4 does not localize to the sites of active autophagy PMID:25554789 FLAG-tagged LIPL-4 protein was localized to intestinal lysosomes (Fig |
| GO:0010508 positive regulation of autophagy | IDA PMID:23392608 Ο-6 Polyunsaturated fatty acids extend life span through the... | ACCEPT | Summary: IDA annotation from CACAO curation of PMID:23392608. O'Rourke et al. showed that LIPL-4 overexpression activates autophagy, and that omega-6 PUFAs produced by LIPL-4 activity are the mediating signals that activate autophagy. Supplementation with omega-6 PUFAs (AA, DGLA) is sufficient to activate autophagy in both C. elegans and human cells. This is also supported by PMID:21906946 which showed that autophagy is induced in animals overexpressing LIPL-4. Reason: Positive regulation of autophagy is a well-established function of LIPL-4, demonstrated in both PMID:23392608 and PMID:21906946. The mechanism involves LIPL-4 producing omega-6 PUFAs that serve as metabolic signals activating autophagy. This is a core biological process downstream of LIPL-4 activity. The evidence code IDA from CACAO is appropriate given that LIPL-4 overexpression directly induces autophagy markers. Supporting Evidence: PMID:23392608 LIPL-4 overexpression is sufficient to not only enrich omega-6 PUFAs and activate autophagy, but also transcriptionally activate nutrient-responsive genes PMID:21906946 autophagy is induced in animals overexpressing LIPL-4 and autophagy is required for their long life span file:worm/lipl-4/lipl-4-deep-research-falcon.md autophagy is needed for elevated lipase activity in germline-less animals, and LIPL-4 is needed for autophagy induction in that model; TOR inhibition induces **lipl-4** expression and lipase activity, linking LIPL-4 to nutrient sensing and autophagy pathways. |
| GO:0004806 triacylglycerol lipase activity | IMP PMID:21906946 Autophagy and lipid metabolism coordinately modulate life sp... | ACCEPT | Summary: IMP annotation of triacylglycerol lipase activity from WormBase curation of PMID:21906946. Lapierre et al. showed that germline-less animals have increased lipase activity that depends on lipl-4, and that lipl-4 RNAi reduces lipase activity in glp-1 mutant background. LIPL-4 was described as a neutral lipase in this paper. Later work (PMID:25554789) confirmed lipid hydrolysis activity at acidic pH and UniProt assigns EC 3.1.1.3 based on the catalytic triad. Reason: Triacylglycerol lipase activity is the core molecular function of LIPL-4. The IMP evidence is based on the observation that lipl-4 RNAi reduces lipase activity in germline-deficient animals. UniProt assigns EC 3.1.1.3 with supporting evidence from PMID:21906946 and PMID:25554789. Supporting Evidence: PMID:21906946 autophagy is required to maintain high lipase activity in germline-deficient animals. Reciprocally, lipl-4 is required for autophagy induction. PMID:25554789 Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants at pH 4.5 but not at pH 7.4 file:worm/lipl-4/lipl-4-deep-research-falcon.md Experimentally, LIPL-4 shows **acid pH-dependent triglyceride lipase activity** and drives **lysosome-derived lipid signaling** that promotes longevity |
| GO:0008340 determination of adult lifespan | IMP PMID:21906946 Autophagy and lipid metabolism coordinately modulate life sp... | ACCEPT | Summary: IMP annotation of determination of adult lifespan from WormBase curation of PMID:21906946. Lapierre et al. showed that lipl-4 is required for lifespan extension in germline-less animals. PMID:25554789 further showed that constitutive overexpression of lipl-4 extends lifespan by 55% and that this requires lysosomal localization. The lifespan effect operates through OEA/NHR-49/NHR-80 signaling and omega-6 PUFA-mediated autophagy activation. Reason: Determination of adult lifespan is a core biological process for LIPL-4. Multiple publications demonstrate that LIPL-4 modulates lifespan: it is required for germline-loss-mediated longevity (PMID:21906946), its overexpression extends lifespan by 55% (PMID:25554789), and the downstream signaling molecules OEA and omega-6 PUFAs are sufficient to extend lifespan (PMID:25554789, PMID:23392608). Supporting Evidence: PMID:21906946 Germline removal extends life span in C. elegans via genes such as the lipase LIPL-4 PMID:25554789 A transgenic strain (lipl-4 Tg) that constitutively expressed lipl-4 in the intestine had 55% mean lifespan increase compared to wild-type (WT) animals file:worm/lipl-4/lipl-4-deep-research-falcon.md Lapierre et al. established that **germline-less (glp-1)** longevity requires **lipl-4**, and that **intestine-specific lipl-4 overexpression** is sufficient to extend lifespan. file:worm/lipl-4/lipl-4-deep-research-falcon.md **+55% mean lifespan** in a constitutive intestinal lipl-4 overexpression strain (lipl-4 Tg) in *Science* 2015. PMID:23392608 Upon fasting, C. elegans induces the expression of a lipase, which in turn leads to an enrichment of omega-6 PUFAs. Supplementing C. elegans culture media with these omega-6 PUFAs increases their resistance to starvation and extends their life span |
| GO:0016239 positive regulation of macroautophagy | IMP PMID:21906946 Autophagy and lipid metabolism coordinately modulate life sp... | ACCEPT | Summary: IMP annotation of positive regulation of macroautophagy from WormBase curation of PMID:21906946. Lapierre et al. showed that lipl-4 is required for autophagy induction in germline-less animals and that LIPL-4 overexpression induces autophagy. PMID:23392608 further demonstrated that omega-6 PUFAs produced by LIPL-4 are the signals that activate autophagy. Reason: This is a more specific child term of GO:0010508 (positive regulation of autophagy), and both are annotated. The macroautophagy specification is appropriate given that the autophagy markers used (LGG-1/LC3, autophagosomes) specifically report on macroautophagy. Both PMID:21906946 and PMID:23392608 provide experimental evidence for this annotation. This represents a core biological process for LIPL-4. Supporting Evidence: PMID:21906946 autophagy is induced in animals overexpressing LIPL-4 and autophagy is required for their long life span, recapitulating observations in germline-less animals file:worm/lipl-4/lipl-4-deep-research-falcon.md autophagy is needed for elevated lipase activity in germline-less animals, and LIPL-4 is needed for autophagy induction in that model PMID:23392608 Supplementation of C. elegans or human epithelial cells with these omega-6 PUFAs activates autophagy, a cell recycling mechanism that promotes starvation survival and slows aging |
| GO:0019433 triglyceride catabolic process | IMP PMID:21906946 Autophagy and lipid metabolism coordinately modulate life sp... | ACCEPT | Summary: IMP annotation of triglyceride catabolic process from WormBase curation of PMID:21906946. LIPL-4 has triacylglycerol lipase activity (EC 3.1.1.3), hydrolyzing triacylglycerols to diacylglycerols and fatty acids. Lapierre et al. showed that lipl-4 contributes to lipase activity in germline-less animals and that autophagy and LIPL-4 interdependently modulate lipid homeostasis. Reason: Triglyceride catabolic process is the direct biological process consequence of LIPL-4 triacylglycerol lipase activity. The annotation is supported by the established catalytic activity (EC 3.1.1.3) and the lipase activity measurements in PMID:21906946. This is a core biological process for LIPL-4. Supporting Evidence: PMID:21906946 autophagy and the lipase LIPL-4 interdependently modulate aging in germline-deficient C. elegans by maintaining lipid homeostasis to prolong life span PMID:25554789 Lipid hydrolysis activity was decreased in lipl-4(tm4417) loss-of-function mutants at pH 4.5 but not at pH 7.4 |
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