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Pathways and mechanisms of endocytic recycling

Key Points

  • Cargo that has been internalized by endocytosis is often recycled to the plasma membrane after being sorted in endosomes.

  • Many proteins and lipids of the plasma membrane are internalized using clathrin-independent mechanisms.

  • Studies of cargo that is internalized independently of clathrin have revealed new pathways and mechanisms of recycling.

  • Precise temporal and spatial regulation of recycling pathways is crucial for diverse cellular processes, including cytokinesis, cell adhesion, morphogenesis, cell fusion, learning and memory.

Abstract

Endocytic recycling is coordinated with endocytic uptake to control the composition of the plasma membrane. Although much of our understanding of endocytic recycling has come from studies on the transferrin receptor, a protein internalized through clathrin-dependent endocytosis, increased interest in clathrin-independent endocytosis has led to the discovery of new endocytic recycling systems. Recent insights into the regulatory mechanisms that control endocytic recycling have focused on recycling through tubular carriers and the return to the cell surface of cargoes that enter cells through clathrin-independent mechanisms. Recent work emphasizes the importance of regulated recycling in processes as diverse as cytokinesis, cell adhesion, morphogenesis, cell fusion, learning and memory.

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Figure 1: Pathways of endocytosis and endocytic recycling.
Figure 2: Recycling and cytokinesis.
Figure 3: Endocytic recycling and long-term potentiation.

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Acknowledgements

We apologize to colleagues whose work we could not cite owing to length restrictions. We thank S. Caplan and members of the Grant and Donaldson laboratories for comments. B.D.G. is supported by National Institutes of Health (NIH) grant R01 GM067237. J.G.D. is supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH.

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Glossary

Macropinocytosis

An actin-dependent process by which cells engulf large volumes of fluids.

Phagocytosis

An actin-dependent process by which cells engulf external particulate material by extension and fusion of pseudopods.

Multivesicular body

An endocytic intermediate organelle in the lysosomal degradative pathway that contains small vesicles and is surrounded by a limiting membrane.

Lipid raft

A microdomain in cellular membranes that is implicated in certain types of endocytosis and signalling and that is enriched in cholesterol and sphingolipids.

ESCRT

(Endosomal sorting complex required for transport). A multiprotein machinery that promotes inward vesiculation at the limiting membrane of the sorting endosome and selects cargo proteins for delivery to the intralumenal vesicles of MVBs.

DENN domain

(Differentially expressed in neoplastic versus normal cells domain). A domain present in many proteins that are involved in vesicle trafficking.

Clathrin-coated pit

The initial site of invagination of a clathrin-coated vesicle.

GTPase-activating protein

A protein that catalyses GTP hydrolysis on GTP-bound proteins.

Immunological synapse

A junction that forms at the contact region between a T cell and its target cells. T cell activation occurs here.

Sorting nexin

A member of a family of proteins that are implicated in membrane trafficking and that contain a Phox domain, which binds to phosphoinositides.

Syndecan

A member of a family of integral membrane heparin sulphate proteoglycans that interact with the extracellular matrix and with growth factors.

PDZ domain

A protein interaction domain that is often found in scaffolding proteins and that is named after the founding members of this protein family (PSD95, Discs large and ZO1).

Guanine nucleotide exchange factor

A protein that facilitates the exchange of GDP (guanine diphosphate) for GTP (guanine triphosphate) in the nucleotide-binding pocket of a GTP-binding protein.

Exocyst

A complex of proteins, forming a membrane tether, that is implicated in exocytosis and is localized to the plasma membrane.

Intercalation

The interdigitation of cells or molecules in a reversible reaction.

Adherens junction

A cell–cell adhesion complex that contains cadherins and catenins that are attached to cytoplasmic actin filaments.

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Grant, B., Donaldson, J. Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol 10, 597–608 (2009). https://doi.org/10.1038/nrm2755

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