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  • Review Article
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The endocytic pathway: a mosaic of domains

Nature Reviews Molecular Cell Biology volume 2, pages 721–730 (2001)Cite this article

Key Points

  • In the endocytic pathway, internalized molecules are delivered to early endosomes, where efficient sorting occurs. Although some molecules, in particular recycling receptors, are rapidly recycled back to the plasma membrane for reutilization; others, including downregulated receptors, are transported to late endosomes and lysosomes for degradation.

  • Early endosomes exhibit a highly pleiomorphic organization, and transport intermediates formed on early endosomal membranes — along recycling and degradation routes — also differ significantly both morphologically and functionally. Selective changes must occur in bilayer organization during biogenesis of these intermediates, and these changes might contribute to protein sorting.

  • Although recycling occurs through thin tubules, transport to late endosomes is mediated by multivesicular intermediates (endosomal carrier vesicles/multivesicular bodies; ECV/MVBs). In addition to this morphologically visible mosaic of membrane domains, key components that regulate membrane organization and protein transport are also distributed in a non-random manner on endosomal membranes.

  • Late endosomes also exhibit a highly pleiomorphic organization, including numerous membrane invaginations with a specific lipid composition. These invaginations seem to have a role not only in cargo degradation, but also in protein–lipid transport through the compartment. Candidate proteins and lipids that regulate the dynamics of these invaginations have been identified.

  • Lysosomes can only be identified at the molecular level by the fact that they lack a few proteins found in late endosomes. Both compartments might represent separate elements of a common dynamic network, involved in sorting and degradation, respectively. Membrane invaginations might have turnpike functions in the network, as they seem to be involved in both transport and degradation.

  • Since a given combination of protein–lipid machines and regulatory factors — but not individual components — seem unique to each endocytic compartment and are distributed non-randomly on membranes, it is attractive to speculate that endosomal membranes are built from modular elements.

Abstract

Organelles in the endocytic pathway are composed of a mosaic of structural and functional regions. These regions consist, at least in part, of specialized protein–lipid domains within the plane of the membrane, or of protein complexes associated with specific membrane lipids. Whereas some of these molecular assemblies can be found in more than one compartment, a given combination seems to be unique to each compartment, indicating that membrane organization might be modular.

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Figure 1: Outline of the endocytic pathway.
Figure 2: The early endosome.
Figure 3: Endosomal carrier vesicles/multivesicular bodies.
Figure 4: Lipid–protein microdomains and molecular machines.
Figure 5: Degradation or recycling?

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Acknowledgements

I am very grateful to G. van der Goot and R. G. Parton for comments and suggestions. Support was by grants from the Swiss National Science Foundation and the International Human Frontier Science Program.

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  1. Department of Biochemistry, University of Geneva, 1211-Geneva-4, Switzerland

    Jean Gruenberg

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DATABASES

Flybase:

Hrs

 Locuslink:

Annexin II

ARF1

ARF6

ARNO

β-COP

CD63

cellubrevin

ɛCOP

EEA1

endobrevin

endosomal COPI complex

Îł-COP

interleukin-2 receptor β chain

LAMP1

M6PR

MLN64

NPC-1

P-selectin

RAB4

RAB5

RAB7

RAB9

Rab11

Rabaptin-5

Rabenosyn-5

RME-1

StAR

syntaxin-6

SNX1

SNX3

SNX15

TIP47

 OMIM:

Niemann–Pick type C

 SGD:

Fab1

VAM7

Vps4

Vps5

Vps27

Vps34

 Swiss-Prot:

CD4

EGFR

syntaxin-13

 Prosite:

FYVE domain

Glossary

CLATHRIN

Large protein, which polymerizes into a triskelion, comprising three heavy chains and three light chains. Triskelions assemble into polyhedral lattices to form clathrin coats.

LIPID RAFTS

Dynamic assemblies of cholesterol and sphingolipids in the plasma membrane, probably involved in cell signalling.

CAVEOLA

Specialized raft that contains the protein caveolin, and forms a flask-shaped, cholesterol-rich invagination of the plasma membrane that might mediate the uptake of some extracellular materials, and is probably involved in cell signalling.

CAVEOSOME

A recently discovered organelle that is involved in the intracellular transport of SV40 from caveolae to the endoplasmic reticulum.

GPI ANCHOR

The function of this post-translational modification is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is linked to the protein through an ethanolamine phosphate moiety.

SNARES

(Soluble N-ethylmaleimide-sensitive factor attachment protein receptor). A family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity in the vacuolar system. They can be divided into vesicle-SNAREs and target-SNAREs on the basis of their localization, or into Q-SNAREs and R-SNAREs on the basis of a highly conserved amino acid.

YEAST CLASS E MUTANTS

One class of vacuolar protein sorting (VPS) mutants in yeast. Class E genes are involved in the delivery of both newly synthesized vacuolar enzyme carBoxypeptidase Y (CPY) and endocytosed proteins to the vacuole from the prevacuolar compartment. Mutations in any of the class E VPS gene products causes an accumulation of cargo in an aberrant endosome-like structure termed the class E compartment.

RETROMER COMPLEX

Protein complex consisting of Vps35, Vps26, Vps29, Vps17 and Vps5, which was discovered through genetic screens in Saccharomyces cerevisiae. It functions in the retrieval of proteins from the prevacuolar compartment and transport to the Golgi.

COPI COAT

Complex consisting of α-, β-, β'-, γ-, δ-, ɛ- and ζ-COP, also called coatomer. This coat complex functions in anterograde transport within the Golgi and in retrograde transport from the Golgi to the endoplasmic reticulum.

COPII COAT

Complex consisting of Sec13, Sec31, Sec23 and Sec24. This coat complex functions in anterograde transport from the endoplasmic reticulum to the Golgi.

LDLF CELLS

A mutant Chinese-hamster ovary cell line that was identified on the basis of its defect in low-density lipoprotein (LDL) transport. The mutation causing the phenotype was later identified as a deletion of É›-COP.

LBPA

Lysobisphosphatidic acid (LBPA) is a phospholipid, structurally analogous with phosphatidylglycerol. LBPA is poorly degradable, presumably because of its unusual stereoconfiguration, and is abundant within internal membranes of late endosomes.

TETRASPANIN FAMILY

The tetraspanin family contains proteins that span the membrane four times with two exoplasmic loops, and that can be found at the cell surface. Although some are highly restricted to specific tissues, others are widely distributed. Members of this family have been implicated in cell activation and proliferation, adhesion, motility, differentiation and cancer.

ANTIGEN-PRESENTING CELLS

A cell, most often a B lymphocyte, macrophage or dendritic cell, that is specialized in the generation of epitopes that are presented through major histocompatibility complex (MHC) class I or II to T lymphocytes.

DENDRITIC CELLS

'Professional' antigen-presenting cells found in T-cell areas of lymphoid tissues, but also as a minor cellular component in most tissues. They have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

MANNOSE 6-PHOSPHATE RECEPTOR

These receptors transport soluble lysosomal hydrolases to late endosomes by cycling between the trans-Golgi network and late endosomes. They bind in the trans-Golgi network to mannose 6-phosphate moieties on N-linked glycans of the hydrolases. They release the hydrolases in late endosomes and return to the trans-Golgi network for another round of transport.

WEIBEL–PALADE BODIES

Morphologically unique secretory structures of endothelial cells, which store von Willebrand factor — a protein involved in blood clotting — for eventual release.

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Gruenberg, J. The endocytic pathway: a mosaic of domains. Nat Rev Mol Cell Biol 2, 721–730 (2001). https://doi.org/10.1038/35096054

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