Rab proteins and Rab-associated proteins: major actors in the mechanism of protein-trafficking disorders

Abstract

Ras-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot-Marie-Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot-Marie-Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be 'prenylated'-i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity.

Conclusion: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.

Fig. 1

The Ras-associated binding (Rab) protein–GTPase cycles. Rab proteins are intrinsically soluble and require a post-translational modification for membrane association. They first associate with a Rab escort protein (REP) and form a stable complex that is the substrate for the subsequent dual prenylation of C-terminal cysteine motifs via Rab geranylgeranyl transferase (RabGGT). RabGGT consists of two different functional subunits (RabGGTα and RabGGTß). After lipid tranfer, REP delivers the prenylated Rab to the donor membrane (the REP cycle is shown with blue arrows). In the absence of REP or RabGGT, Rab proteins remain in the cytosol in an inactive state. The transfer of Rab proteins between acceptor and donor membranes is facilitated by the GDP dissociation inhibitor (GDI) (the GDI cycle is shown with red arrows). Both REP and GDI bind the GDP-bound inactive form of Rab. After REP or GDI dissociate from Rabs at the donor membrane, Rabs can cycle between the inactive (GDP-bound) and active (GTP-bound) states. Rab proteins are activated by guanine nucleotide exchange factors (RabGEFs) and deactivated by GTPase activating proteins (RabGAPs), which accelerate the slow intrinsic rates of nucleotide exchange and GTP hydrolysis. In the active state, Rabs interact with structurally and functionally diverse effectors, including cargo sorting complexes on donor membranes, motor proteins involved in vesicular transport and tethering complexes that regulate vesicle fusion with acceptor membranes

Fig. 2

Regulation of aquaporin-2 (AQP2)-mediated water transport by vasopressin (AVP). Shown is a nephron with a magnified principal cell. In this cell, the vasopressin V2 receptor (V2R), stimulatory GTP binding protein (Gs), adenylate cyclase (AC), ATP, cAMP, and phosphorylated proteins (O-P) are indicated. This figure has been used with permission of the American Journal of Physiology and Renal Physiology