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Lysosomes as dynamic regulators of cell and organismal homeostasis

Nature Reviews Molecular Cell Biology volume 21, pages 101–118 (2020)Cite this article

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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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Fig. 1: Properties of lysosomes.
Fig. 2: The lysosome as a signalling hub.
Fig. 3: The role of TFEB in the transcriptional regulation of the lysosomal–autophagic pathway.
Fig. 4: Lysosome–organelle interactions.
Fig. 5: Membrane contacts between lysosomes and other organelles.
Fig. 6: Machineries involved in lysosome motility.

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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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Authors and Affiliations

  1. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy

    Andrea Ballabio

  2. Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy

    Andrea Ballabio

  3. Ian and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Andrea Ballabio

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Andrea Ballabio

  5. Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Juan S. Bonifacino

Authors
  1. Andrea Ballabio
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  2. Juan S. Bonifacino
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Andrea Ballabio or Juan S. Bonifacino.

Ethics declarations

Competing interests

A.B. is a co-founder of CASMA Therapeutics (Boston, MA, USA). J.S.B. declares no competing interest.

Additional information

Peer review informationNature Reviews Molecular Cell Biology thanks R. Puertollano, S. Ferguson, J. Klumperman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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