Lysosome-to-nucleus lipid signaling in Caenorhabditis elegans

In the Caenorhabditis elegans intestine, lysosomes send lipid signals to the nucleus that adjust fat metabolism and extend lifespan. The TFEB ortholog HLH-30 is a basic helix-loop-helix transcription factor that moves into the nucleus during fasting, after germline loss or when TOR signalling falls. It turns on autophagy and lysosome genes, and with the Max-like factor MXL-3 it links lysosomal lipolysis to nutrient supply. The lysosomal acid lipase LIPL-4, a homolog of human LIPA, is induced in these conditions and hydrolyses lipids at acidic pH inside the lysosome. Its activity raises the levels of omega-6 polyunsaturated fatty acids, which promote autophagy, and of the N-acylethanolamine oleoylethanolamide (OEA). The intestinal fatty acid-binding protein LBP-8 sits on lysosomes and binds OEA and oleic acid with high affinity. When LIPL-4 activity is high, LBP-8 enters the nucleus through an N-terminal nuclear localization signal. There, OEA binds the HNF4-family nuclear receptor NHR-80 directly. NHR-80 works with its partner NHR-49, which does not bind OEA, to switch on genes for fatty acid desaturation (fat-5, fat-6, fat-7) and mitochondrial beta-oxidation (acs-2), as well as lbp-8 itself. The pathway is needed for the long life of animals that overexpress LIPL-4 or LBP-8. It is independent of dietary restriction.

Boundary. This is a concrete C. elegans signalling module with four parts in order: (1) HLH-30/TFEB transcriptional control of the lysosomal and autophagy program, an upstream input that induces lipl-4; (2) LIPL-4 lipolysis in the lysosomal lumen; (3) LBP-8 lipid transfer from lysosome to nucleus; (4) the NHR-80/NHR-49 nuclear receptor pair that sets transcription of desaturase and beta-oxidation genes. Downstream target enzymes (FAT-5/6/7 delta-9 desaturases, ACS-2) are listed as targets but not modelled as annotons, because they are not reviewed and they are a metabolic output rather than part of the signal. The later mitochondrial step (ETC complex II, mtROS, JUN-1; PMID:30713071) is also outside the boundary. Excluded members. NHR-47 was considered and excluded: its gene review finds no published link to lysosomal lipid signalling, OEA or NHR-49/80. NHR-66 (NHR-49 partner for sphingolipid and remodelling genes) and NHR-13 are not part of the OEA axis. DAF-16 and PHA-4 regulate lipl-4 and autophagy genes in germline-less animals, but they belong to germline longevity signalling, not this module. MXL-3 and the NAPE-PLDs NAPE-1/2 appear in the text but have no reviews. Relation to MODULE:metazoan_autophagosome_biogenesis. HLH-30 induces autophagy genes (lgg-1, lgg-2, sqst-1, atg-18), and the omega-6 PUFAs that build up with LIPL-4 activity promote autophagy (PMID:23392608). Autophagy is in turn needed to keep lipase activity high in germline-less animals (PMID:21906946). The autophagy machinery itself is modelled in the autophagosome module. Here it is only the context that HLH-30 and the PUFA branch feed into. OEA source caveat. LIPL-4 is a triacylglycerol lipase, but OEA is made by NAPE-specific phospholipase D, and nape-1 loss only halves the longevity of LIPL-4 or LBP-8 overexpression. The LIPL-4 annoton therefore asserts only lipase activity, and the link from LIPL-4 to OEA is a PROVIDES_INPUT_FOR connection, not a reaction product of LIPL-4.