Trends in Molecular Medicine
ReviewRab GTPases, intracellular traffic 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.
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