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Signals from the lysosome: a control centre for cellular clearance and energy metabolism
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Signals from the lysosome: a control centre for cellular clearance and energy metabolism
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Journal Article
Signals from the lysosome: a control centre for cellular clearance and energy metabolism
2013
Overview
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
PPAR
α (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.
As well as degrading and recycling cellular waste, lysosomes are involved in secretion, plasma membrane repair, signalling and energy metabolism. The identification of transcription factor EB (TFEB) as a central regulator of lysosomal biogenesis and autophagy provides insight into how lysosomes adapt to environmental cues, and targeting TFEB may be a promising therapeutic strategy for modulating lysosomal function in disease.
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.
