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ARF proteins: roles in membrane traffic and beyond

Nature Reviews Molecular Cell Biology volume 7, pages 347–358 (2006)Cite this article

Key Points

  • The unique cellular distribution of individual ADP-ribosylation factor (ARF) proteins and the molecules with which they interact are vital in dictating ARF-protein function. The mutually exclusive properties in cellular distribution and function of mammalian ARF1 and ARF6 have been extensively investigated. However, parallels in the cellular roles of both these ARF proteins in vesicle budding and actin remodelling is becoming increasingly evident.

  • ARF1–GTP drives COPI-mediated vesicle budding along the biosynthetic and secretory pathway. ARF1 also regulates the formation of clathrin-coated vesicles at the trans-Golgi network by promoting the recruitment of adaptor-protein complexes AP-1, AP-3, AP-4, and the GGAs from the cytosol onto membranes. ARF1 activation has been shown to stimulate the assembly of spectrin and the actin cytoskeleton on Golgi membranes.

  • Nucleotide exchange on ARF is regulated by the Sec7-domain-containing GEFs. Site-specific targeting of GBF- and BIG-family GEFs to Golgi subcompartments might have a prominent role in the formation of coats at specific locations. Membrane lipid composition and temporal aspects of vesicle budding can affect the targeting of ARF1 to Golgi membranes.

  • GTP hydrolysis on ARF1 is required for the dissociation of coat proteins from transport vesicles, and is mediated by a family of ARF GAPs. GTP-hydrolysis on ARF1 is also required for cargo packaging, and ARF GAPs might function to couple cargo sorting with vesicle formation.

  • ARF6 localizes to the plasma membrane and endosomal compartments, in which it regulates clathrin-dependent endocytic membrane trafficking, as well as the trafficking and sorting of molecules that lack cytoplasmic AP-2 and clathrin sorting sequences, through a unique endocytic route. ARF6 has also been implicated in actin remodelling at the cell periphery. The effects of ARF6 on the actin cytoskeleton are thought to occur through the activation of the Rac1 GTPase and/or its effect on phopholipid metabolism.

  • The ARF6-GTPase cycle can impinge on several cellular events that require rapid changes in cell-surface morphology and as such, directly impinges on cellular processes such as phagocytosis, cell–cell adhesion, cell migration, tumour-cell invasion and cytokinesis.

Abstract

The ADP-ribosylation factor (ARF) small GTPases regulate vesicular traffic and organelle structure by recruiting coat proteins, regulating phospholipid metabolism and modulating the structure of actin at membrane surfaces. Recent advances in our understanding of the signalling pathways that are regulated by ARF1 and ARF6, two of the best characterized ARF proteins, provide a molecular context for ARF protein function in fundamental biological processes, such as secretion, endocytosis, phagocytosis, cytokinesis, cell adhesion and tumour-cell invasion.

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Figure 1: Regulation of COPI-coat assembly and vesicle budding by ARF1.
Figure 2: Regulation of actin assembly by ARF1 during vesicle formation at the Golgi.
Figure 3: ARF6 regulates clathrin-dependent and clathrin-independent endocytic pathways.
Figure 4: Multiple roles for ARF6 at the cell periphery.
Figure 5: ARF6-mediated regulation of Rac1 activation in epithelial cells.

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Acknowledgements

We are grateful to members of our laboratories for many helpful discussions and comments on the manuscript. We apologize to investigators whose work is not cited or indirectly cited owing to space constraints.

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Authors and Affiliations

  1. Department of Biological Sciences and the Walther Cancer Institute, University of Notre Dame, Notre Dame, Indiana, USA

    Crislyn D'Souza-Schorey

  2. Membrane and Cytoskeleton Dynamics Group, UMR 144 CNRS/Institut Curie, Paris, France

    Philippe Chavrier

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  1. Crislyn D'Souza-Schorey
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Glossary

GTPase-activating protein

A protein that promotes (up to 1000-fold) low intrinsic GTPase activity of GTP-binding proteins.

Guanine nucleotide-exchange factor

A protein that facilitates the exchange of bound GDP for GTP on a GTP-binding protein.

Switch regions

Two regions (Switch-I and -II) that undergo extensive conformational changes from the GDP- to the GTP-bound form of small GTP-binding proteins. In the GTP-bound conformation the switch regions mediate binding to the effector proteins.

Clathrin

A large protein that polymerizes into a triskelion that consists of three heavy chains and three light chains. Triskelions assemble into polyhedral lattices to form clathrin coats.

Actin

An ∼42-kDa globular protein that polymerizes into filaments. Actin filaments organize to form the actin-cytoskeleton network. The actin cytoskeleton is an important determinant of cell shape and is rapidly remodelled during cellular processes such as cell migration and cell division.

Phagocytosis

A receptor-mediated and actin-based process that allows the internalization and clearance of particulate material (> 0.5 μm) by specialized cell types such as macrophages, dendritic cells and neutrophils.

Coat protein complex I

A seven-subunit complex that consists of α-,β-,β′-, γ-, δ-, ε- and ζ-COP, which is also called coatomer. This coat complex functions in anterograde transport within the Golgi and in retrograde transport from the Golgi to the endoplasmic reticulum.

Endosome

A membrane transport vesicle that is formed after molecules are internalized by endocytosis.

Sec7 domain

A ∼200-amino-acid catalytic domain that was initially identified in the yeast protein Sec7 and is conserved in all ARF GEFs.

Brefeldin A

(BFA). A fungal metabolite that causes a rapid dissociation of ARF1, COPI and clathrin-coat adaptor proteins from Golgi membranes. BFA prevents completion of the nucleotide exchange reaction of Sec7-domain-containing GEFs through a non-competitive mechanism in which the drug traps the Sec7 domain together with GDP-bound ARF proteins in an abortive complex.

SNARE

Soluble N-ethylmaleimide-sensitive factor attachment-protein receptor. A family of membrane-tethered coiled-coil proteins that regulate fusion reactions and dictate 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.

KDEL

A C-terminal motif of Lys-Asp-Glu-Leu (KDEL) on certain soluble endoplasmic reticulum (ER) proteins that functions as a recognition motif for the KDEL receptor. The KDEL receptor mediates the retrieval of KDEL proteins that have leaked to the Golgi complex, back to the ER.

Phospholipase D

(PLD). An enzyme that catalyses the hydrolysis of the phosphodiester bond of phosphatidyl choline to generate phosphatidic acid (PA) and free choline. PA has signalling properties. In mammals, there are two PLD isoforms, PLD1 and PLD2, both of which are subject to complex regulation by lipid cofactors, protein kinases and GTP-binding proteins of the ARF and Rho subfamilies.

Endocytosis

The internalization of molecules into the cell from the extracellular environment.

Caveolae

Specialized membrane invaginations that form from lipid rafts and contain high amounts of cholesterol and sphingolipids. They are thought to compartmentalize signalling molecules and also facilitate non-clathrin-mediated endocytosis.

Cytokinesis

Division of the cell cytoplasm. Cytokinesis completes the cell cycle and creates membrane barriers between two daughter cells, each with a complete array of chromosomes and intracellular organelles.

Proteasome

A cytoplasmic enzyme complex that degrades cytosolic and transmembrane proteins that have been marked for destruction by ubiquitin tagging or by some other means.

Rho family GTPases

A subfamily of small (∼21 kDa) GTP-binding proteins that are related to Ras and that regulate the cytoskeleton.

Adherens junctions

Epithelial cell–cell-type junction complex that contains E-cadherin and the catenin-family proteins. The cytoplasmic tail is coupled to the actin cytoskeleton.

Invadopodia

Actin-rich membrane protrusions that are formed at the adherent cell surface of migrating cells as they invade the extracellular matrix. Invadopodia recruit various enzymes such as metalloproteinases and serine proteases to degrade matrix proteins and form the invasive front of the cell. Invadopodia are enriched in integrins and associated signalling proteins.

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D'Souza-Schorey, C., Chavrier, P. ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol 7, 347–358 (2006). https://doi.org/10.1038/nrm1910

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