A lysosome-centered view of nutrient homeostasis

Abstract

Lysosomes are highly acidic cellular organelles traditionally viewed as sacs of enzymes involved in digesting extracellular or intracellular macromolecules for the regeneration of basic building blocks, cellular housekeeping, or pathogen degradation. Bound by a single lipid bilayer, lysosomes receive their substrates by fusing with endosomes or autophagosomes, or through specialized translocation mechanisms such as chaperone-mediated autophagy or microautophagy. Lysosomes degrade their substrates using up to 60 different soluble hydrolases and release their products either to the cytosol through poorly defined exporting and efflux mechanisms or to the extracellular space by fusing with the plasma membrane. However, it is becoming evident that the role of the lysosome in nutrient homeostasis goes beyond the disposal of waste or the recycling of building blocks. The lysosome is emerging as a signaling hub that can integrate and relay external and internal nutritional information to promote cellular and organismal homeostasis, as well as a major contributor to the processing of energy-dense molecules like glycogen and triglycerides. Here we describe the current knowledge of the nutrient signaling pathways governing lysosomal function, the role of the lysosome in nutrient mobilization, and how lysosomes signal other organelles, distant tissues, and even themselves to ensure energy homeostasis in spite of fluctuations in energy intake. At the same time, we highlight the value of genomics approaches to the past and future discoveries of how the lysosome simultaneously executes and controls cellular homeostasis.

Keywords: C elegans; amino acid; homeostasis; human; hydrolase; lipid; lysosome; metabolism; nutrient; sensor; yeast.

Figure 1.

The lysosome is a nutrient-sensing center. When nutrients are sufficient (upper panel), amino acids induce structural changes in the lysosomal vacuolar-type ATPase (V-ATPase), so that it weakens its association with the Ragulator-RAG complex. Thus, Ragulator-RAG can recruit MTOR to the lysosomal membrane. The small GTPase RHEB that resides at the lysosomal membrane, can now stimulate the phosphorylation and consequent activation of MTOR. RRAGA/B facilitates MTOR activation and recruitment of TFEB to the lysosome for its phosphorylation and retention in the cytoplasm by YWHA chaperones. When nutrients are scarce (bottom panel), the RAG GTPases recruit TSC (tuberous sclerosis complex), which converts GTP-RHEB to GDP-RHEB causing inactivation and release of MTOR into the cytosol. Fasting stimulates AMPK, which in turn activates the TSC complex. In addition, since MTOR phosphorylates the MiTs transcription factors, upon MTOR inhibition, these transcriptional regulators are not phosphorylated and are free to translocate to the nucleus and activate genes involved in lysosomal biogenesis and function.

Figure 2.

Long-range signals from the lysosome coordinate nutrient homeostasis. The lysosome generates signals that travel to activate cell autonomous or systemic responses that promote nutrient homeostasis. Some of these signaling pathways are depicted here: I. Cholesterol uptake and synthesis is controlled from the lysosome. Cholesterol is taken up and processed by the lysosomal system. When the lysosome releases enough cholesterol, the transcription factor SREBF/SREBP is in the ER. By contrast, low cholesterol promotes SREBF trafficking from the ER to the Golgi (not shown), and then to the nucleus where it transcribes genes involved in lipid uptake and biosynthesis. II. Lysosome fatty-acid derivatives distally control autophagy and the transcription of β-oxidation genes. In C. elegans, fasting leads to increased lysosomal lipase activity (LIPL-4). Increased LIPL-4 activity is capable of: 1) generating lipid signals including ω-3 and ω-6 polyunsaturated fatty acids (ω-FA) and oleoylethanolamide (OEA), 2) inhibiting LET-363/MTOR, 3) activating autophagy, and 4) inducing β-oxidation and other metabolic genes through NHR-49 and NHR-80. ω-3 and ω-6 polyunsaturated fatty acids are transported to distant tissues by LBP-3 and LBP-5, and OEA is transported to the nucleus by LBP-8. Green arrows indicate unconfirmed activation during fasting conditions. Dotted lines illustrate likely pathways that have not been directly tested (intermediate steps are likely). III. Lysosomal calcium activates lysosomal biogenesis and autophagy. Starvation triggers calcium release from the lysosome through the MCOLN1 channel. Calcium then activates the phosphatase PPP3/calcineurin, which dephosphorylates TFEB promoting its translocation to the nucleus where it transcribes genes involved in lysosomal biogenesis and autophagy. LAL, lysosomal acid lipases.

Figure 3.

The lysosome is a nutrient sensing, processing and signaling center. The lysosome is the only organelle that receives nutrients and nutritional information from the cell (autophagy) and from the environment (endocytosis). Some of the roles of the lysosome in nutrient homeostasis include: I) sensing of nutrients and growth factors by the Lysosome Nutrient Sensing (LYNUS) machinery, II) digestion and recycling of circulating nutrients (i.e., cholesterol), growth factors (i.e., GH1 [growth hormone 1]), and nutrient regulators (i.e., perilipins); III) digestion and recycling of intracellular macromolecules and organelles; IV) recycling of growth factors, growth factor receptors (i.e., for GH1 and insulin), and nutrient receptors (i.e., LDLR/LDL receptor), V) coordination of responses to fluctuations in nutrient availability by releasing signaling molecules that activate homeostatic responses (i.e., cholesterol biosynthesis or activation of autophagy) locally and in distant cells and tissues; VI) controlling its own biogenesis, and VII) storage. All together, these functions provide building blocks and energy units to promote growth and reproduction, but most importantly the lysosome integrates nutritional information from the cell and the environment so that growth and reproduction are only promoted when conditions are favorable to do so.