Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans

Abstract

Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm, Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, consequently promoting longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids whose abundance was increased in worms constitutively over-expressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…NHR‐49 dimerizes with NHR‐13, NHR‐66, and NHR‐80 to regulate genes involved in lipid metabolism (Folick et al., 2015; Pathare et al., 2012). However, the tBOOH‐induced expression of fmo‐2 , K05B2.4, and icl‐1 was largely unchanged in nhr‐13 ( ok796 ), nhr‐66 ( ok940 ), and nhr‐80 ( tm1011 ) null mutants (Figure S2a).…”

“…NHR‐49 is a critical regulator of lipid metabolism and longevity (Burkewitz et al., 2015; Chamoli, Singh, Malik & Mukhopadhyay, 2014; Folick et al., 2015; Khan et al., 2013; Ratnappan et al., 2014; Seah et al., 2016), while related nuclear receptors, HNF4 and PPARα, are therapeutic targets that share at least some of these functions in mammals. Here, we show that NHR‐49 is also vital for an adaptive transcriptional response to the organic peroxide tBOOH.…”

Protein Quality Control in Health and Disease

“…Recently, a lysosome-to-nucleus mechanism was discovered in C. elegans (Folick et al 2015). This signaling pathway shares key features with the HSR and UPR pathways.…”

Cell Biology of theCaenorhabditis elegansNucleus

“…In addition to DAF-16, regulated nucleocytoplasmic transport of other longevity factors is presumably also involved in life span determination. Recently, the small intracellular fatty acid binding protein, LBP-8, was reported to mediate signaling from lysosomes to the nucleus and thereby activate genes that act positively in longevity (Folick et al 2015). LBP-8 contains a predicted NLS, and a relative large deletion that removes this sequence (but potentially also other functions of LBP-8) abolishes LBP-8's capacity to increase life span (Folick et al 2015).…”