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Sorting GPI-anchored proteins

Nature Reviews Molecular Cell Biology volume 5, pages 110–120 (2004)Cite this article

Key Points

  • Glycosylphosphatidylinositol (GPI)-anchored proteins are attached to the lumenal side of membranes of the secretory and endocytic pathways by a glycolipid anchor. As they are not exposed to the cytoplasm, the mechanism of their sorting in the secretory/endocytic system does not fit the normal model of interaction of cytosolic sorting signals with the proteins that are involved in vesicle formation.

  • The GPI anchor endows the protein with the ability to associate with specialized membrane microdomains that are referred to as lipid rafts. It might also carry information that is important for trafficking of the GPI-anchored proteins.

  • After exiting the endoplasmic reticulum (ER), GPI-anchored proteins are segregated into vesicles that are distinct from those carrying other secretory and plasma membrane proteins. Proteins that were previously shown to be required for tethering and fusion of ER-derived vesicles with the Golgi compartment have been shown to have an additional function in GPI-anchored-protein sorting.

  • GPI-anchored proteins are found in very small microdomains at the plasma membrane. They can be internalized from the cell surface by a clathrin and dynamin-independent pinocytic pathway into specialized endosomes by a process that depends on a Rho-family GTPase.

  • GPI-anchored-protein sorting in the endocytic pathway is strongly influenced by lipid composition — in particular, the amounts of cholesterol and sphingolipids, which are components of lipid rafts. Stabilization of the association with lipid-raft domains might be a crucial factor in the retention of GPI-anchored proteins in the endocytic pathway.

  • A common two-step model is proposed for GPI-anchored-protein sorting in the secretory/endocytic pathways. First, GPI-anchored proteins are laterally segregated from other membrane proteins; second, they are concentrated into budding vesicles.

Abstract

The study of glycosylphosphatidylinositol-anchored-protein sorting has led to some surprising new findings and concepts. Evidence is accumulating that, during their delivery to the surface, different types of plasma membrane protein might be sorted from each other early in this pathway, in the endoplasmic reticulum. Furthermore, membrane-lipid composition and microdomains might have a role in the process of protein sorting in both the secretory and endocytic pathways.

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Figure 1: GPI-anchored-protein precursor and anchor structure.
Figure 2: A model of GPI-anchored-protein sorting.
Figure 3: GPI-anchored proteins are internalized into pinosomes by a dynamin-independent mechanism.
Figure 4: Endocytosis of GPI-anchored proteins from the cell surface.

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Acknowledgements

Research in S. Mayor's laboratory was supported by a Senior Research Fellowship from The Wellcome Trust, the Department of Biotechnology (India), and intra-mural funds from the National Centre for Biological Sciences, India. S.M. is grateful to V. Sriram, S. Sabharanjak, S. Chatterjee and P. Sharma and other members of the laboratory for their invaluable contributions to this review. Research in H. Riezman's laboratory was supported by grants from the Swiss National Science Foundation, Human Frontiers Science Program Organization, and the Office Fédéral de l'Education et de la Science. H.R. is grateful to members of his laboratory for critical reading of the review.

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Authors and Affiliations

  1. National Centre for Biological Sciences, UAS-GKVK Campus, Bangalore, 560065, India

    Satyajit Mayor

  2. Department of Biochemistry, University of Geneva, Sciences II, 30 quai Ernest Ansermet, Geneva, CH-1211, Switzerland

    Howard Riezman

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DATABASES

LocusLink

PIGA

OMIM

Paroxysmal nocturnal haemoglobinuria

Saccharomyces genome database

bet1

bos1

Emp24

ERV29

Gas1

sec22

SEC34

Uso1

YOS9

Ypt1

Swiss-Prot

CD14

LBP

p115

uPA

uPAR

Glossary

ISOPRENOIDS

Compounds that are derived from isoprene (2-methylbuta-1,3-diene) linked together in head-to-tail or tail-to-tail conformations and that comprise farnesyl and geranylgeranyl molecules that are used in the covalent modification of proteins on cysteine residues.

COMPLEMENT

Nine interacting serum proteins (C1–C9) — which are mostly enzymes — that are activated in a coordinated way and participate in bacterial lysis and macrophage chemotaxis.

COAT PROTEINS

Molecules that form a proteinaceous coating around vesicles that are used in membrane trafficking. They are believed to be important for vesicle formation and recruitment of cargo into the forming vesicles.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). The non-radiative transfer of energy from a donor fluorophore to an acceptor fluorophore that is typically <80 Å away. FRET will only occur between fluorophores in which the emission spectrum of the donor has a significant overlap with the excitation of the acceptor.

NSF

(N-ethylmaleimide-sensitive fusion protein). NSF was originally isolated because of its requirement for vesicle fusion in vitro. It is associated with SNAPs (soluble NSF accessory proteins).

PRO-ALPHA FACTOR

A yeast pheromone precursor that is produced by haploid mating-type-a cells.

COG COMPLEX

A protein complex that is conserved from yeast to mammalian cells and is found on the Golgi compartment. Its precise function is not yet known, but it seems to be important for various steps of membrane trafficking to, and through, the Golgi.

SNARE PROTEINS

Soluble NSF (N-ethylmaleimide-sensitive fusion protein) accessory protein (SNAP) receptors on the membrane. SNARE proteins have been implicated as determinants of the specific fusion of vesicles with target membranes. They have been classified into two complementary classes that are referred to as vesicle-membrane SNAREs (v-SNAREs) and target-membrane SNAREs (t-SNAREs).

APICAL DOMAIN

A domain in the plasma membrane of epithelial cells that is exposed to the external environment.

N-GLYCANS

Carbohydrate molecules that are linked to asparagine moieties in proteins. They have several possible structures and are built on a common core structure that is composed of N-acetylglucosamine and mannoses.

CLATHRIN

The first vesicle coat protein to be identified. It is involved in membrane traffic to, and through, the endocytic pathway.

DYNAMIN

A high-molecular-weight GTPase that is thought to be involved in the 'pinching off' of vesicles from membranes.

PINCHING OFF

The process whereby vesicles are detached from membranes.

CAVEOLAE

Small plasma-membrane invaginations that occur in many cell types, in particular in endothelial cells. Caveolae are usually coated with a protein of the caveolin family.

LIPOPOLYSACCHARIDE

(LPS). A bacterial surface glycolipid that is often a primary antigen and effector during bacterial infections.

HAEMOCYTES

Blood cells, particularly of insects and crustacea. They are similar in many respects to leukocytes, as they are phagocytic and are not involved in oxygen transport.

RABS

Small Ras-like GTPase molecules that are implicated in regulating membrane-trafficking dynamics by recruiting effector molecules.

GEEC

(GPI-anchored-protein-enriched early endosomal compartments). It accounts for a main fraction of the fluid phase of the endocytic content, and is formed independently of dynamin function.

CDC42

A small Rho-family GTPase that is implicated in localized actin dynamics in cells.

TOXIN B

A Clostridium difficile toxin that irreversibly inactivates all Rho-family GTPases by glucosylation.

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Mayor, S., Riezman, H. Sorting GPI-anchored proteins. Nat Rev Mol Cell Biol 5, 110–120 (2004). https://doi.org/10.1038/nrm1309

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