Abstract
Exciting new discoveries have transformed the view of the lysosome from a static organelle dedicated to the disposal and recycling of cellular waste to a highly dynamic structure that mediates the adaptation of cell metabolism to environmental cues. Lysosome-mediated signalling pathways and transcription programmes are able to sense the status of cellular metabolism and control the switch between anabolism and catabolism by regulating lysosomal biogenesis and autophagy. The lysosome also extensively communicates with other cellular structures by exchanging content and information and by establishing membrane contact sites. It is now clear that lysosome positioning is a dynamically regulated process and a crucial determinant of lysosomal function. Finally, growing evidence indicates that the role of lysosomal dysfunction in human diseases goes beyond rare inherited diseases, such as lysosomal storage disorders, to include common neurodegenerative and metabolic diseases, as well as cancer. Together, these discoveries highlight the lysosome as a regulatory hub for cellular and organismal homeostasis, and an attractive therapeutic target for a broad variety of disease conditions.
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Acknowledgements
The authors thank A. De Matteis, G. Diez-Roux, P. Luzio, R. Mattera, G. Napolitano and C. Settembre for comments on the manuscript and J. Goodwin for the original draft of Fig. 3a. Work in A.B.’s laboratory is supported by the US National Institutes of Health (R01-NS078072), the Italian Association for Cancer Research (AIRC) (IG 2018 22103), Fondation Louis-Jeantet and the Telethon Foundation. Work in J.S.B.’s laboratory is supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (ZIA HD001607).
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A.B. is a co-founder of CASMA Therapeutics (Boston, MA, USA). J.S.B. declares no competing interest.
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Glossary
- Membrane contact sites
-
Membrane domains where organelles are closely (10–30 nm) held together by tethering proteins.
- RAG GTPases
-
RAGA, RAGB, RAGC and RAGD are small GTPases that belong to a subfamily of the RAS-related GTPases. They act as heterodimers in which RAGA or RAGB interacts with RAGC or RAGD. Their activation by amino acids mediates the recruitment of mechanistic target of rapamycin complex 1 to the lysosomal surface.
- Ragulator
-
Protein complex composed of five subunits (LAMTOR1–LAMTOR5). It is located on the lysosomal surface, where it interacts with RAG GTPases for the recruitment of mechanistic target of rapamycin complex 1 to the lysosome. It also interacts with BORC for the regulation of lysosome positioning.
- Tuberous sclerosis complex
-
(TSC). Protein complex, composed of TSC1 (hamartin), TSC2 (tuberin) and TBC1D7, which functions as a GTPase-activating protein for the small GTPase RHEB.
- Folliculin
-
(FLCN). Tumour-suppressor protein that exists as part of a complex with the folliculin-interacting protein and functions as a GTPase-activating protein for the RAGC and RAGD GTPases.
- Endolysosomes
-
Generic term for various types of endosomes and lysosomes.
- Sphingosine
-
Long-chain unsaturated amino alcohol that forms the backbone of a class of membrane lipids known as sphingolipids.
- Phosphoinositide
-
A class of phospholipids comprising a myo-inositol head group linked by a glycerol moiety to two fatty acyl chains. Phosphoinositides are minor components of cellular membranes involved in signalling and regulation of membrane dynamics.
- 14-3-3 proteins
-
Family of proteins that bind phosphorylated serine or threonine residues on various regulatory proteins such as kinases, phosphatases, transcription factors and signal-transduction proteins.
- Hyperuricaemia
-
Elevated levels of uric acid in blood.
- Lysosomotropic drugs
-
Drugs that concentrate within the acidic lumen of lysosomes and modify lysosomal function.
- Pyroptosis
-
A type of programmed cell death most often triggered by infection with intracellular pathogens and mediated by pore-forming gasdermin D, which permeabilizes the plasma membrane.
- Ferroptosis
-
Iron-dependent form of cell death triggered by inactivation of cellular glutathione-dependent antioxidant defences with consequent accumulation of lipid reactive oxygen species.
- Necroptosis
-
A programmed form of necrosis that is downstream of cell-death receptor signalling, which is generally induced by cell damage but can also be promoted by lysosomal membrane permeabilization.
- Galectin protein family
-
Endogenous carbohydrate-binding proteins (lectins) with specificity for β-galactoside sugars.
- Tripartite motif (TRIM) protein family
-
Family of E3 ubiquitin ligases having RING, B-box and coiled-coil domains.
- AMPK
-
AMP-activated protein kinase that functions as a master regulator of cellular energy metabolism.
- ESCRT machinery
-
Ensemble of complexes known as endosomal sorting complexes required for transport that perform various membrane bending and scission reactions away from the cytoplasm.
- Toll-like receptor (TLR) family
-
Family of transmembrane receptors that recognize pathogen-associated molecular patterns as part of the innate immune response.
- Pathogen-associated molecular patterns
-
Microbial molecules that trigger innate immune responses.
- Nuclear factor-κB
-
Family of transcription factors that regulate the expression of genes involved in both innate and adaptive immunity.
- Interferon regulatory factors
-
Transcription factors that control both innate and adaptive immunity against invading pathogens.
- SNAREs
-
Soluble N-ethylmaleimide-sensitive factor attachment protein receptors, which orchestrate membrane fusion events in the cytoplasm.
- Oleoylethanolamide
-
(OEA). Monounsaturated fatty acid ethanolamide that functions as a bioactive lipid in many physiological processes.
- Nuclear hormone receptors
-
Ligand-activated receptors that bind to specific DNA sequences and regulate gene transcription.
- β-oxidation
-
Catabolic process by which fatty acids are broken down to generate acetyl-CoA in mitochondria.
- MiT-TFE family
-
Family of helix–loop–helix leucine zipper transcription factors that regulate expression of genes involved in the biogenesis and function of lysosomes and autophagosomes.
- Unfolded protein response
-
Cellular stress response triggered by accumulation of unfolded proteins in the endoplasmic reticulum.
- Spermidine
-
Organic polycation that regulates various cellular processes, including translation.
- Vacuolar ATPase
-
(v-ATPase). Multisubunit, ATP-driven proton pump responsible for the acidification of intracellular compartments.
- Tethering complex
-
Protein complex that promotes SNARE-dependent fusion of membrane-bound organelles.
- Atg8/LC3/GABARAP family
-
Homologues of yeast autophagy-related protein 8 (Atg8); ubiquitin-like proteins that function in cargo recruitment to autophagosomes and autophagosome–lysosome fusion.
- RHEB
-
Member of the RAS family of small GTPases that is mainly involved in activation of mechanistic target of rapamycin complex 1.
- Retrograde movement
-
In general, movement from the plus end to the minus end of microtubules; in the axon, movement from the axon terminal towards the cell body.
- Anterograde movement
-
In general, movement from the minus end to the plus end of microtubules; in the axon, movement from the cell body towards the axon terminal.
- CORVET
-
Tethering complex composed of six subunits (VPS3, VPS8, VPS11, VPS16, VPS18 and VPS33) that functions in endosomal fusion events.
- Neurofibrillary tangles
-
Intraneuronal aggregates of hyperphosphorylated tau protein that are most commonly associated with Alzheimer disease.
- α-Synuclein
-
Presynaptic protein pathogenetically linked to Parkinson disease.
- Pompe disease
-
Lysosomal storage disorder caused by acid α-glucosidase deficiency, which results in accumulation of glycogen in the cells.
- Gaucher disease
-
Lysosomal storage disorder caused by deficiency of glucocerebrosidase, which results in the build-up of glucocerebroside in the cells.
- Lewy bodies
-
Abnormal deposits of the protein α-synuclein in the brain of patients with various neurodegenerative disorders, including Lewy body dementia, Parkinson disease and Alzheimer disease.
- Presenilin 1
-
One of the four subunits of the γ-secretase complex. The encoding gene is mutated in an inherited form of Alzheimer disease.
- Amyloid precursor protein
-
(APP). Transmembrane protein that is proteolytically processed to various products, including amyloid-β peptide involved in Alzheimer disease.
- mTORC2
-
Protein complex comprising the mechanistic target of rapamycin kinase and five additional subunits (MLST8, DEPTOR, MSIN1, PROTOR and RICTOR) that functions in the regulation of cellular metabolism and growth.
- Netrin
-
Secreted protein that functions in cell migration and cell–cell and cell–extracellular matrix interactions.
- Anchor cells
-
Cells that participate in the development of the reproductive system in Caenorhabditis elegans.
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Ballabio, A., Bonifacino, J.S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol 21, 101–118 (2020). https://doi.org/10.1038/s41580-019-0185-4
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DOI: https://doi.org/10.1038/s41580-019-0185-4
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