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A lysosome-centered view of nutrient homeostasis.

Mony VK, Benjamin S, O'Rourke EJ - Autophagy (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: a Department of Biology , College of Arts and Sciences, University of Virginia , Charlottesville , VA , USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.110 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).112 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),80,112 2) inhibiting LET-363/MTOR,113 3) activating autophagy,112,113 and 4) inducing β-oxidation and other metabolic genes through NHR-49 and NHR-80.80 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.116 LAL, lysosomal acid lipases.
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f0002: 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.110 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).112 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),80,112 2) inhibiting LET-363/MTOR,113 3) activating autophagy,112,113 and 4) inducing β-oxidation and other metabolic genes through NHR-49 and NHR-80.80 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.116 LAL, lysosomal acid lipases.

Mentions: As described in section 2, cholesteryl esters are taken up by receptor-mediated endocytosis, and degraded through the action of LIPA to release cholesterol through specialized transporters. In addition to being a precursor of many metabolites and a structural component of membranes, cholesterol released from the lysosomes also functions as a signaling molecule. The SREBF (sterol regulatory element binding transcription factor) proteins control the expression of genes involved in lipid uptake and biosynthesis.107 When lysosome-derived cholesterol levels are high, SREBF resides in the ER, bound to SCAP (SREBF chaperone) and INSIG1 (Fig. 2).108-110 Low cholesterol levels lead to dissociation of INSIG1, freeing the SREBF-SCAP complex to traffic to the Golgi where it is cleaved by the proteases MBTPS1/S1P and MBTPS2/S2P. Free SREBF translocates to the nucleus to activate the transcription of genes involved in lipid uptake and biosynthesis.110 Conversely, binding of cholesterol to SCAP inhibits cleavage of the SREBF-SCAP complex. In this way, lysosomal cholesterol represses its own synthesis. Additionally, an excess of lysosome-derived cholesterol causes activation of the transcription factor NR1H/LXR (nuclear receptor subfamily 1 group H), which transcribes genes involved in the removal of cholesterol from cells.111 Thus, sterol signals originated in the lysosome are an integral part of cholesterol homeostasis.Figure 2.


A lysosome-centered view of nutrient homeostasis.

Mony VK, Benjamin S, O'Rourke EJ - Autophagy (2016)

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.110 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).112 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),80,112 2) inhibiting LET-363/MTOR,113 3) activating autophagy,112,113 and 4) inducing β-oxidation and other metabolic genes through NHR-49 and NHR-80.80 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.116 LAL, lysosomal acid lipases.
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Related In: Results  -  Collection

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f0002: 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.110 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).112 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),80,112 2) inhibiting LET-363/MTOR,113 3) activating autophagy,112,113 and 4) inducing β-oxidation and other metabolic genes through NHR-49 and NHR-80.80 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.116 LAL, lysosomal acid lipases.
Mentions: As described in section 2, cholesteryl esters are taken up by receptor-mediated endocytosis, and degraded through the action of LIPA to release cholesterol through specialized transporters. In addition to being a precursor of many metabolites and a structural component of membranes, cholesterol released from the lysosomes also functions as a signaling molecule. The SREBF (sterol regulatory element binding transcription factor) proteins control the expression of genes involved in lipid uptake and biosynthesis.107 When lysosome-derived cholesterol levels are high, SREBF resides in the ER, bound to SCAP (SREBF chaperone) and INSIG1 (Fig. 2).108-110 Low cholesterol levels lead to dissociation of INSIG1, freeing the SREBF-SCAP complex to traffic to the Golgi where it is cleaved by the proteases MBTPS1/S1P and MBTPS2/S2P. Free SREBF translocates to the nucleus to activate the transcription of genes involved in lipid uptake and biosynthesis.110 Conversely, binding of cholesterol to SCAP inhibits cleavage of the SREBF-SCAP complex. In this way, lysosomal cholesterol represses its own synthesis. Additionally, an excess of lysosome-derived cholesterol causes activation of the transcription factor NR1H/LXR (nuclear receptor subfamily 1 group H), which transcribes genes involved in the removal of cholesterol from cells.111 Thus, sterol signals originated in the lysosome are an integral part of cholesterol homeostasis.Figure 2.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: a Department of Biology , College of Arts and Sciences, University of Virginia , Charlottesville , VA , USA.

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.

No MeSH data available.


Related in: MedlinePlus