Lysosomes: Signaling Hubs for Metabolic Sensing and Longevity

Abstract

Lysosomes are sites of active metabolism in a cell. They contain various hydrolases that degrade extracellular and intracellular materials during endocytosis and autophagy, respectively. In addition to their long-recognized roles in degradation and recycling, emerging studies have revealed that lysosomes are organizing centers for signal transduction. Lysosome-derived signaling plays crucial roles in regulating nutrient sensing, metabolic adaptation, organelle crosstalk, and aging. In particular, how the degradative role of the lysosome cooperates with its signaling functions to actively modulate lifespan is beginning to be unraveled. This review describes recent advances in the role of the lysosome as a 'signaling hub' that uses three different lysosome-derived signaling pathways to integrate metabolic inputs, organelle interactions, and the control of longevity.

Keywords: AMPK signaling; aging and longevity; lipid messenger signaling; lysosome-to-nucleus signaling; mTOR signaling.

Key Figure, Figure 1.. Lysosomal signaling pathways in longevity regulation

Genetic or pharmacological modification of three lysosomal signaling pathways promotes longevity. Positive regulators labeled in blue show genes whose induction extend lifespan, and negative regulators labeled in orange show genes whose inhibition extend lifespan.

Figure 2.. Lysosomal lumen amino acid sensing by mTORC1.

In the presence of amino acids, specific amino acids (arginine) within the lysosomal lumen directly bind to SLC38A9 and signal through v-ATPase-Ragulator complex to promote the GTP binding state of RagA/B. Moreover, cytosolic amino acids activate the FLCN-FNIP complex resulting in GTP hydrolysis in RagC/D. The Rag GTPase heterodimer in the state of RagA/B^GTP-RagC/D^GDP recruits mTORC1 to the lysosome surface where Rheb resides. Rheb stimulates mTORC1 activity toward downstream substrates. The TSC complex localized at the lysosome surface functions as GAP of Rheb to negatively regulate mTORC1. Activated mTORC1 phosphorylates multiple downstream substrates, and several examples are listed.

Figure 3.. Glucose sensing of AMPK on lysosome surface

Upon glucose depletion, the level of fructose 1,6-biphosphate (FBP) derived from the glycolysis pathway decreases. The glycolytic enzyme aldolase, which normally binds to the v-ATPase complex in FBP-loading state on the lysosome surface, becomes unoccupied upon FBP deprivation. The dissociation of FBP alters the interaction between aldolase and the v-ATPase-Ragulator complex, resulting in the formation of a protein complex consisting of the v-ATPase, Ragulator, AXIN, LKB1, and AMPK at the lysosome surface and the activation of AMPK. Activated AMPK phosphorylates multiple downstream substrates, and several examples are listed.

Figure 4.. Lysosome to nucleus lipid messenger signaling

Overexpression of lysosomal acid lipase LIPL-4 induces oleoylethanolamine (OEA) and fatty acid binding protein LBP-8. The translocation of LBP-8 from the lysosome surface into the nucleus presents OEA to its nuclear receptor NHR-80, which cooperates with another nuclear receptor NHR49 to induce the transcription of target genes such as lbp-8, acs-2 and acdh-1.