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Signals from the lysosome: a control centre for cellular clearance and energy metabolism

Key Points

  • Lysosomes are cellular organelles involved in the degradation and recycling of cellular waste. Extracellular and intracellular materials to be degraded reach the lysosome via endocytosis and autophagy, respectively. Lysosomes are also involved in secretion and plasma membrane repair, by fusing to the plasma membrane in a process termed lysosomal exocytosis.

  • Lysosomal function is performed by lumenal hydrolases that are responsible for substrate digestion and by membrane-associated proteins that handle trafficking of materials into and out of the lysosome.

  • A complex machinery, which includes the kinase complex mammalian target of rapamycin complex 1 (mTORC1, a major regulator of cell growth), the vesicular ATPase complex and additional complexes, is located on the lysosomal surface and is devoted to sensing the nutrient content of the lysosome. This complex is called the lysosomal nutrient sensing (LYNUS) machinery.

  • Most genes encoding lysosomal proteins belong to a gene network termed CLEAR (coordinated lysosomal expression and regulation), and they are transcriptionally regulated by transcription factor EB (TFEB), the master regulator for lysosomal biogenesis. Using this regulatory mechanism, cells can adapt lysosomal function to respond to environmental cues.

  • The activity of TFEB is induced following starvation, by both transcriptional autoregulation and a phosphorylation-dependent mechanism. Once activated, TFEB mediates the starvation response by activating lipid catabolism via the regulation of the master lipid metabolism genes PPARα (peroxisome proliferator-activated receptor-α) and PGC1α (PPARγ co-activator 1α). TFEB regulation and function are conserved in worms.

  • Lysosomal and autophagy dysfunction occurs both in lysosomal storage diseases (LSDs) and in common neurodegenerative diseases, resulting in defective cellular clearance and the accumulation of toxic material. Thus, TFEB-mediated induction of cellular clearance may represent an attractive therapeutic strategy for these disorders.

Abstract

For a long time, lysosomes were considered merely to be cellular 'incinerators' involved in the degradation and recycling of cellular waste. However, now there is compelling evidence indicating that lysosomes have a much broader function and that they are involved in fundamental processes such as secretion, plasma membrane repair, signalling and energy metabolism. Furthermore, the essential role of lysosomes in autophagic pathways puts these organelles at the crossroads of several cellular processes, with significant implications for health and disease. The identification of a master regulator, transcription factor EB (TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the lysosome adapts to environmental cues, such as starvation, and targeting TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease.

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Figure 1: Main functions of the lysosome and their relationship with key cellular processes.
Figure 2: Model of TFEB regulation and function during starvation.
Figure 3: Defective cellular clearance in neurodegenerative diseases.
Figure 4: TFEB regulates cellular clearance.

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Acknowledgements

The authors thank T. Braulke, A. De Matteis, J. Irazoqui, D. Rubinsztein, D. Sabatini, P. Saftig and R. Zoncu for the helpful suggestions, G. Diez-Roux for helpful discussions and support during manuscript preparation and E. Abrams for manuscript editing. They acknowledge the support of the Italian Telethon Foundation (TGM11CB6, to C.S. and A.B), the Beyond Batten Disease Foundation (to C.S. and A.B.), the European Research Council Advanced Investigator (250154, to A.B.), March of Dimes (#6-FY11-306, to A.B) and the US National Institutes of Health (R01-NS078072, to A.B).

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Glossary

Glycocalyx

The polysaccharide-based coating on the inner side of a lysosomal membrane that protects this organelle from digestion by lysosomal enzymes.

Autophagosomes

Intracytoplasmic vacuoles that contain elements of the cytoplasm of a cell. They fuse with lysosomes, and the contents are subjected to enzymatic digestion.

Danon disease

An X-linked dominant disorder caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP2). It predominantly affects cardiac muscle.

Niemann–Pick disease type C1

An autosomal recessive lipid storage disorder that is caused by mutation in the NPC1 (Niemann Pick type C1) gene. It is characterized by progressive neurodegeneration.

Lysosome-related organelles

(LROs). Cell type-specific compartments that include melanosomes, lytic granules, major histocompatibility complex class II compartments, platelet-dense granules, basophil granules, azurophil granules and Drosophila melanogaster pigment granules.

Wolman's disease

An early-onset fulminant disorder of infancy with substantial infiltration of several organs, including the spleen and the liver, by macrophages filled with cholesteryl esters and triglycerides. It is caused by mutations in the gene encoding lipase A.

Multiple sulphatase deficiency

(MSD). An autosomal recessive inherited disease that is caused by mutations in the sulphatase-modifying factor 1 (SUMF1) gene.

Mucopolysaccharidosis

(MPS). A metabolic disorder that is caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules.

Gaucher's disease

An autosomal recessive lysosomal storage disorder due to the deficient activity of β-glucocerebrosidase.

Fronto-temporal dementia

A disorder associated with fronto-temporal lobar degeneration.

Charcot–Marie–Tooth type 2B

Autosomal dominant peripheral sensory neuropathy due to mutations in the late endosomal small GTPase RAB7.

Neuronal ceroid lipofuscinosis

A clinically and genetically heterogeneous group of neurodegenerative disorders that are characterized by the intracellular accumulation of autofluorescent lipopigment storage material.

Pompe's disease

An autosomal recessive inherited disease, also known as glycogen storage disease II. This prototypic lysosomal storage disease is caused by mutations in the gene encoding acid α-1,4-glucosidase.

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Settembre, C., Fraldi, A., Medina, D. et al. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14, 283–296 (2013). https://doi.org/10.1038/nrm3565

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