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Rab GTPases as coordinators of vesicle traffic

Key Points

  • Rab GTPases control all aspects of intracellular vesicle trafficking by acting as regulatable switches that recruit effector molecules when in their active GTP-bound form.

  • There are approximately 60 different Rab GTPases in humans that are associated with distinct intracellular membranes.

  • Rab GTPases are turned on and off by specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), respectively.

  • Rab effectors come in many forms and range from vesicle tethers to motors, kinases, phosphatases and various adaptor proteins.

  • Different Rab GTPases are restricted to distinct subdomains of the same organelle membrane and can crosstalk through effectors that are coupled to GEFs or GAPs.

  • Rab GTPases are essential for physiological processes such as immunity, hormone secretion and neurotransmission, and their genetic inactivation is associated with diseases.

Abstract

Membrane trafficking between organelles by vesiculotubular carriers is fundamental to the existence of eukaryotic cells. Central in ensuring that cargoes are delivered to their correct destinations are the Rab GTPases, a large family of small GTPases that control membrane identity and vesicle budding, uncoating, motility and fusion through the recruitment of effector proteins, such as sorting adaptors, tethering factors, kinases, phosphatases and motors. Crosstalk between multiple Rab GTPases through shared effectors, or through effectors that recruit selective Rab activators, ensures the spatiotemporal regulation of vesicle traffic. Functional impairments of Rab pathways are associated with diseases, such as immunodeficiencies, cancer and neurological disorders.

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Figure 1: The Rab switch and its circuitry.
Figure 2: Localization and function of Rab GTPases.
Figure 3: Rab GTPase functions in vesicle trafficking.
Figure 4: Rab domains.
Figure 5: Coordination of Rab functions.
Figure 6: Rab modulation of receptor signalling.

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Acknowledgements

I thank M. Zerial for introducing me to the fascinating world of Rabs. Work in my laboratory is generously supported by the Research Council of Norway, the Norwegian Cancer Society, the South-Eastern Norway Regional Health Authority and the European Union.

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DATABASES

OMIM

Charcot-Marie-Tooth disease type 2B

choroideremia

GS1

GS2

GS3

Martsolf syndrome

type II diabetes

Warburg Micro syndrome

InterPro

FYVE

TBC

FURTHER INFORMATION

Harald Stenmark's homepage

Glossary

SNARE

(Soluble N-ethylmaleimide-sensitive factor attachment protein receptor). A small membrane protein on the vesicle membrane or the target membrane that forms a tetrahelical bundle with two or three other SNAREs on opposing membranes, thereby causing membrane docking and fusion.

Guanine nucleotide exchange factor

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

GTPase-activating protein

A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP.

GDP dissociation inhibitor

A protein that prevents GDP release from Rab- and Rho- family GTPases and regulates the cycling of these GTPases between the membrane and the cytosol.

Clathrin-coated pit

A small invagination of the plasma membrane that is covered with a clathrin lattice on the cytosolic side and is about to form a clathrin-coated endocytic vesicle.

Myosin V family

A subfamily of the myosin family of motor proteins that 'walk' towards the barbed (plus) end of actin filaments and typically mediate vesicle movement from the cell centre to the periphery.

Kinesin superfamily

A superfamily of motor proteins that (with a few exceptions) move vesicles and other cargoes towards the plus (polymerizing) end of microtubules.

Cytoplasmic dynein

A large microtubule motor that moves vesicles and other cargoes towards the minus (depolymerizing) end of microtubules.

Exocyst

An octameric protein complex that is involved in targeting post-Golgi vesicles to the plasma membrane.

COPII vesicle

An endoplasmic reticulum- derived vesicle, coated with the heterotetrameric COPII protein complex, that is involved in biosynthetic transport to the Golgi.

Microdomain

In the context of this Review, a small membrane domain (0.2–1.0 μm in length) that can be distinguished by light microscopy.

Retromer

A heteropentameric protein complex that mediates vesicle transport between early endosomes and the trans-Golgi network.

Tight junction

A circumferential ring at the apex of epithelial cells that is formed by multiprotein complexes from two adjoining cells. It keeps the respective plasma membranes of the cells close together, creating a fluid-impermeable barrier.

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Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10, 513–525 (2009). https://doi.org/10.1038/nrm2728

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