Review
Rab GTPases, intracellular traffic and disease

https://doi.org/10.1016/S1471-4914(01)02227-4Get rights and content

Abstract

Membrane and protein traffic in the secretory and endocytic pathways is mediated by vesicular transport. Recent studies of certain key regulators of vesicular transport, the Rab GTPases, have linked Rab dysfunction to human disease. Mutations in Rab27a result in Griscelli syndrome, caused by defects in melanosome transport in melanocytes and loss of cytotoxic killing activity in Tcells. Other genetic diseases are caused by partial dysfunction of multiple Rab proteins resulting from mutations in general regulators of Rab activity; Rab escort protein-1 (choroideremia), Rab geranylgeranyl transferase (Hermansky–Pudlak syndrome) and Rab GDP dissociation inhibitor-α (X-linked mental retardation). In infectious diseases caused by intracellular microorganisms, the function of endocytic Rabs is altered either as part of host defences or as part of survival strategy of the pathogen. The human genome is predicted to contain 60 RAB genes, suggesting that future work could reveal further links between Rab dysfunction and disease.

Section snippets

Rab GTPases

Rab proteins (also known as Ypt in yeasts and plants) are monomeric GTPases of the Ras superfamily (reviewed in Refs 7, 8, 9). Recent analyses indicate that Rabs are present in all eukaryotes and the Rab families in the genomes of several species have been reported 10, 11, 12. Currently 60 human RAB genes are known (see Table 1). However, the complexity of the Rab protein family might be even greater as there is evidence that alternative splicing of Rab genes results in the production of

How do Rabs regulate transport?

By analogy to other GTPases, Rabs are thought to act as molecular switches cycling between GTP-bound (active) and GDP-bound (inactive) conformations. In the active state, Rabs recruit a diverse group of proteins termed ‘effector’ proteins to the cytoplasmic leaflet of the membrane. Recruitment of effector proteins might enable Rabs to control the main steps in vesicular transport, including cargo selection and budding, movement, docking and fusion (Fig. 1) 7, 8, 9. When Rabs switch conformation

Rabs in human genetic disease: Rab27a and Griscelli syndrome

To date, Rab27a is the only example of a Rab specifically implicated in a human genetic disease. Griscelli syndrome (GS) is a rare autosomal recessive disorder characterized by pigment dilution of the hair (silvery hair), owing to the accumulation of pigment in melanocytes, and haemophagocytic syndrome caused by uncontrolled T-cell and macrophage activation 17, 18. Immune deficiency does not feature in all cases as GS is phenotypically and genetically heterogeneous. The majority of GS patients

Rabs in human genetic disease: Rab regulators and diseases of multiple Rab dysfunction

Several genetic diseases result from mutations in genes encoding general regulators of the function of all Rabs, for example Rab escort protein (REP), Rab geranylgeranyl transferase (RabGGT) and RabGDI. REP and RabGGT catalyse lipid modification and initial membrane association of Rabs (Fig. 2) [14]. RabGDI is postulated to extract GDP-bound Rabs from target membranes and maintain them in the GDP-bound state as a cytosolic reservoir for reuse, eventually delivering them back to the donor

Rabs, the phagocytic pathway and infectious disease

In addition to diseases resulting directly from mutation of genes encoding Rab regulators and Rab27a, there is now evidence linking alteration in Rab function and the progression of acquired diseases. For instance, alteration of the activity of Rab proteins controlling endocytosis could be an important factor in the pathogenesis of diseases caused by intracellular microorganisms.

Many intracellular bacterial, fungal and protozoan parasites are engulfed by their host cell, usually a macrophage,

Future directions

The study of Rab GTPases, their regulators and effectors has already generated valuable insights into human diseases, as described here. Indeed, it is likely that many more examples linking Rab dysfunction and disease will emerge in the coming years, for the following reasons. First, Rabs appear to serve crucial roles in vesicular transport and much evidence indicates that they profoundly influence the biochemical composition and biological activity of the membrane upon which they reside, via

Acknowledgements

We thank all members of our laboratory for helpful ideas and comments, and David Holden for critical reading of the manuscript. Further thanks to Jane Stinchcombe for the generous gift of the CTL photographs shown in Fig. 4 and Jose Ramalho for help with Table 1. Our work is supported by the Wellcome Trust, the Medical Research Council and the Foundation Fighting Blindness.

References (65)

  • E.K. Novak

    Inherited thrombocytopenia caused by reduced platelet production in mice with the gunmetal pigment gene mutation

    Blood

    (1995)
  • T. Sasaki

    Purification and characterization from bovine brain cytosol of a protein that inhibits the dissociation of GDP from the subsequent binding of GTP to smg p25A, a ras p21-like GTP-binding protein

    J. Biol. Chem.

    (1990)
  • C. Alvarez-Dominguez et al.

    Interferon-gamma selectively induces Rab5a synthesis and processing in mononuclear cells

    J.Biol. Chem.

    (1998)
  • C. Alvarez-Dominguez et al.

    Increased expression of Rab5a correlates directly with accelerated maturation of Listeria monocytogenes phagosomes

    J. Biol. Chem.

    (1999)
  • A. Prada-Delgado

    Interferon-gamma listericidal action is mediated by novel Rab5a functions at the phagosomal environment

    J. Biol. Chem.

    (2001)
  • L.E. Via

    Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by rab5 and rab7

    J. Biol. Chem.

    (1997)
  • K. Mukherjee

    SopE acts as a Rab5-specific nucleotide exchange factor and recruits non-prenylated Rab5 on Salmonella-containing phagosomes to promote fusion with early endosomes

    J. Biol. Chem.

    (2001)
  • G.H. Xiao

    The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis

    J. Biol. Chem.

    (1997)
  • V.M. Olkkonen et al.

    Role of Rab GTPases in membrane traffic

    Int. Rev. Cytol.

    (1997)
  • V.M. Olkkonen et al.

    Genetic defects of intracellular-membrane transport

    New Engl. J. Med.

    (2000)
  • M. Aridor et al.

    Traffic jam: a compendium of human diseases that affect intracellular transport processes

    Traffic

    (2001)
  • T. Hackstadt

    Redirection of host vesicle trafficking pathways by intracellular parasites

    Traffic

    (2000)
  • S. Méresse

    Controlling the maturation of pathogen-containing vacuoles: a matter of life and death

    Nat. Cell Biol.

    (1999)
  • L.A. Knodler

    Pathogenic trickery: deception of host cell processes

    Nat. Rev. Mol. Cell Biol.

    (2001)
  • M. Zerial et al.

    Rab proteins as membrane organizers

    Nat. Rev. Mol. Cell Biol.

    (2001)
  • Stenmark, H. and Olkkonen, V.M. (2001) The Rab GTPase family. Genome Biol. 2, reviews...
  • J.B. Bock

    A genomic perspective on membrane compartment organization

    Nature

    (2000)
  • A. Echard

    Alternative splicing of the human Rab6A gene generates two close but functionally different isoforms

    Mol. Biol. Cell

    (2000)
  • Y. Takai

    Small GTP-binding proteins

    Physiol. Rev.

    (2001)
  • C. Alroy et al.

    Organization of the rab-gdi/chm superfamily: the functional basis for choroideremia disease

    Traffic

    (2001)
  • C. Griscelli et al.

    Pigment dilution and immunodeficiency: a new syndrome

    Int. J. Dermatol.

    (1978)
  • G. Menasche

    Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome

    Nat. Genet.

    (2000)
  • Cited by (0)

    View full text