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Lysosomes: fusion and function

Key Points

  • Lysosomes are dynamic organelles that receive membrane traffic input from the secretory, endocytic, autophagic and phagocytic pathways. They can also fuse with the plasma membrane.

  • Live-cell imaging has shown that lysosomes interact with late endosomes by 'kiss-and-run' events and by direct fusion. Fusion results in the formation of hybrid organelles, in which the degradation of endocytosed macromolecules occurs and from which lysosomes are re-formed.

  • The use of yeast genetics and mammalian cell-free systems has identified much of the protein machinery that is involved in the delivery of macromolecules to lysosomes. The fusion of late endosomes with lysosomes involves tethering, the formation of trans-SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complexes and phospholipid bilayer fusion.

  • Conventional lysosomes may fuse with the plasma membrane in response to a rise in cytosolic Ca2+ and can provide the additional membrane required for plasma-membrane wound repair. Specialized secretory lysosomes and lysosome-related organelles exist in some cell types.

  • Lysosomes may also fuse with phagosomes and autophagosomes. Some phagocytosed pathogens can prevent or delay phagolysosome biogenesis; others escape their intracellular vacuole by degrading the phagosomal membrane and may evade autophagy or reside in autophagic compartments and delay the formation of autolysosomes.

  • Upregulating autophagic pathways and the formation of autophagolysosomes provides the prospect of therapies for a range of proteinopathies including Huntington's disease and Parkinson's disease.

Abstract

Lysosomes are dynamic organelles that receive and degrade macromolecules from the secretory, endocytic, autophagic and phagocytic membrane-trafficking pathways. Live-cell imaging has shown that fusion with lysosomes occurs by both transient and full fusion events, and yeast genetics and mammalian cell-free systems have identified much of the protein machinery that coordinates these fusion events. Many pathogens that hijack the endocytic pathways to enter cells have evolved mechanisms to avoid being degraded by the lysosome. However, the function of lysosomes is not restricted to protein degradation: they also fuse with the plasma membrane during cell injury, as well as having more specialized secretory functions in some cell types.

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Figure 1: Delivery to lysosomes and lysosomal fusion.
Figure 2: Electron microscopy of endosome–lysosome fusion.
Figure 3: Schematic models of heterotypic late endosome–lysosome fusion and homotypic late endosome fusion.
Figure 4: Secretory lysosomes in cytotoxic T lymphocytes.
Figure 5: Pathogen survival by avoidance of lysosomes.

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Acknowledgements

Unpublished experimental work referred to in this article was funded by a Research Grant to J.P.L from the Medical Research Council. The Cambridge Institute for Medical Research is supported by a Strategic Award from the Wellcome Trust. We thank M. Gratian for help with live-cell imaging and preparation of the lysosome–endosome animations.

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DATABASES

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Huntington's disease

mucolipidosis type IV

Parkinson's disease

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Lysosome–endosome fusion

Glossary

Endosome

A membrane-bound compartment (organelle) to which ligands, membrane components and fluid are delivered following internalization (endocytosis) from the cell surface.

Membrane whorl

A membranous structure that has the appearance of being multi-lamellar or arranged in spirals when observed in cross-section.

Autophagy

A process by which cytoplasmic components, including organelles, can be sequestered into autophagosomes and subsequently degraded.

Phagosome

A membrane-bound compartment containing particles such as bacteria, yeast or parasites that have been internalized from the cell surface by the process of phagocytosis.

Autophagosome

An intracellular compartment that is formed when a double membrane sequesters a portion of cytoplasm that often includes organelles. Autophagosomes subsequently fuse with lysosomes.

trans-Golgi network

A tubulovesicular structure on the trans side of the stack of Golgi cisternae where cargo molecules are sorted to different secretory destinations.

Multivesicular body

An endosome that contains many vesicles in the lumen of each organelle. It can also be called a late endosome.

Dominant-negative mutant

A protein encoded by a mutated gene that prevents the function of the wild-type protein in cells in which both the mutant and wild-type proteins are expressed at the same time.

Liposome

An artificial lipid vesicle that encloses an aqueous interior.

Isopycnic ultracentrifugation

Centrifugation of samples (organelles or macromolecules) in a density gradient until an equilibrium is reached, such that the density of the sample is the same as that part of the density gradient in which it equilibrates.

Retromer complex

A complex of cytoplasmic proteins that are required for some retrograde membrane-trafficking pathways that deliver cargo from endosomes to the trans-Golgi network.

Parasitophorous vacuole

A membrane-bound organelle that contains an intracellular parasite; the membrane that surrounds the organelle is derived from the host cell but is modified by the parasite to facilitate its survival and growth.

Melanosome

A membrane-bound organelle that contains melanin and is formed in melanocytes.

Basophil granule

A granule in white blood cells that stains with basophilic dyes.

Immunological synapse

A specialized contact area between a T lymphocyte and an antigen-presenting cell.

Alpha granule

A platelet granule that contains several growth factors, clotting proteins and the adhesion molecule P-selectin.

Phagosomal cup

A cup-shaped structure, formed principally by invagination of the plasma membrane during the early stages of phagocytic uptake of particles by cells. Membrane that originates from other organelles may be added to it.

Macropinosome

A membrane-bound compartment (organelle), often of 0.5 μm diameter or larger. It is formed during fluid-phase uptake, particularly in regions of the cell where plasma-membrane ruffling occurs.

α-2,8-linked polysialic acid

A linear homopolymer of N-acetyl neuraminic acid monomers that are linked by α-2,8 ketosidic linkages.

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Luzio, J., Pryor, P. & Bright, N. Lysosomes: fusion and function. Nat Rev Mol Cell Biol 8, 622–632 (2007). https://doi.org/10.1038/nrm2217

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