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Endocytic recycling

Key Points

  • A typical fibroblast cell is estimated to internalize at least 2% of its plasma membrane into endosomes per minute. The return of membrane from endosomes to the cell surface is necessary for the maintenance of membrane homeostasis.

  • Some membrane proteins (for example, activated growth-factor receptors, the low-density-lipoprotein receptor and the transferrin receptor) are internalized by a concentrative mechanism in which the receptors are localized to specialized, clathrin-coated regions of the plasma membrane. Concentration in clathrin-coated pits is determined by the interaction of specific sequences (motifs) in the cytoplasmic domains of the proteins with elements of the coated pits.

  • There are two main fates for materials that are internalized into sorting endosomes — they can be delivered to degradative late endosomes and lysosomes or returned to the plasma membrane.

  • Most membrane proteins are returned to the cell surface by a mechanism that, unlike internalization through clathrin-coated pits, is not generally dependent on a specific sequence that signals a protein for recycling. In fact, the efficient targeting of a membrane protein to late endosomes or other intracellular destinations requires a specialized targeting motif. Most non-membrane-bound material inside sorting endosomes (for example, low-density lipoprotein) is delivered to late endosomes and lysosomes.

  • As well as to internalize nutrient receptors and activated receptors, endocytic uptake has an important role in the retrieval of transmembrane proteins of the biosynthetic organelles. The localization of many proteins to these organelles is based on a dynamic retrieval process.

  • In addition to constitutive endocytic uptake and recycling, the trafficking some proteins through the endosomal system is regulated. Regulated trafficking provides a means by which a cell can rapidly and specifically modulate the expression of proteins on the plasma membrane. One important example of this is the regulation by insulin of the GLUT4 glucose transporter on the surface of fat and muscle cells.

Abstract

After endocytosis, most membrane proteins and lipids return to the cell surface, but some membrane components are delivered to late endosomes or the Golgi. We now understand that the pathways taken by internalized molecules that eventually recycle to the cell surface can be surprisingly complex and can involve a series of sorting events that occur in several organelles. The molecular basis for many of these sorting processes is only partly understood.

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Figure 1: Modes of internalization.
Figure 2: Endocytic recycling pathways.
Figure 3: The iterative, geometric sorting endosome.
Figure 4: Functional recycling without removal from the plasma membrane.

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Acknowledgements

The work in the authors' laboratories is supported by grants from the National Institutes of Health.

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DATABASES

Interpro

amphyphysin

dynamin

Swiss-Prot

ARF6

CI-MPR

β-COP

ε-COP

EEA1

EHD1

endophilin

Furin

GGA2

HRS

PECAM

Rab5

Rab6a′

Rab11

TGN38

Ubiquitin

VAMP3

Glossary

TRANSCYTOSIS

The process in which materials are transported across a polarized cell by internalization from one membrane domain (for example, the basolateral membrane), passage through the endosomal/recycling system and eventual delivery to the other domain (for example, the apical membrane).

SORTING ENDOSOMES

Tubular–vesicular structures that receive direct input from coated-pit-derived endocytosis. They have a key role in sorting material for recycling or degradation.

ENDOCYTIC RECYCLING COMPARTMENT

(ERC). A component of the endocytic recycling system. A large fraction of recycling membrane components pass through the ERC, which is mainly composed of narrow diameter tubules. In some cells, the ERC is organized around the microtubule-organizing centre.

SNAREs

(soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein (SNAP) receptors). SNARE proteins function in cognate pairs, with one set of the pair being localized to the vesicle and the other to the target membrane. The resultant SNARE pair has a role in the fusion of the bilayer. Assembly of the proper SNARE pair is also involved in establishing the specificity of fusion.

AP1/μ1B ADAPTOR COMPLEX

A form of adaptor protein 1 (AP1) that is expressed in polarized cells and that has a role in polarized endocytic recycling.

LIPID MICRODOMAINS

Localized membrane regions that differ from surrounding regions in their lipid composition and order. There are probably many types of lipid microdomain that coexist within the same membrane bilayer. One type of microdomain is a lipid raft.

INSULIN-REGULATED COMPARTMENT

A specialized endosomal compartment found in fat and muscle cells. This poorly described compartment is the site of storage of the glucose transporter GLUT4. Insulin recruits GLUT4 to the plasma membrane from this compartment.

MEMBRANE-ORDER PARAMETERS

These parameters describe the organization and dynamics of lipids in a bilayer. Highly ordered lipids have tight packing and restricted motion of the hydrocarbon core.

LIPID RAFTS

One type of lipid microdomain that is characterized by a relatively high content of cholesterol, sphingomyelin and glycosphingolipids. These microdomains are resistant to solubilization by non-ionic detergent because of their tight packing. They resemble liquid-ordered domains that are found in model membranes, which are characterized by tight packing and the high lateral mobility of lipids within the bilayer.

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Maxfield, F., McGraw, T. Endocytic recycling. Nat Rev Mol Cell Biol 5, 121–132 (2004). https://doi.org/10.1038/nrm1315

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