Rab GTPases implicated in inherited and acquired disorders

Abstract

The endocytotic machinery imports, transports and exports receptors and associated molecules between the plasma membrane and various cytoplasmic chambers resulting in selective recycling, degradation, or secretion of molecules and signaling complexes. Trafficking of receptors, growth factors, nutrients, cytokines, integrins as well as pathogens dictates the kinetics and magnitude of signal transduction cascades. Understandably, alterations in the 'fate' of such cargo complexes have profound physiologic and pathophysiologic implications. Rab GTPases regulate endocytosis by decorating intracellular vesicles and targeting these vesicles along with their cargoes to appropriate subcellular compartments. In the last decade, the number of genetic diseases driven by germline mutations in Rab GTPases or their interacting proteins, has increased and there is growing evidence of aberrant Rab GTPase function in acquired pathophysiologies such as immune deficiency, infection, obesity, diabetes and cancer.

Figure 1. RabGTPases Mediated Vesicular Trafficking

Rab GTpases are involved in trafficking of cell membrane receptors including RTKs, GLUT4 and integrins. Rab5 facilitates fusion of clathrin-coated vesicles containing activated receptor to EE. The cargo is then sorted either to Rab4 decorated vesicles for fast-track recycling or to Rab11 decorated long loop slow recyling endosomes. Alternatively, for attenuation of signal transduction, the cargo laden vesicles are targetted to the lysosome via Rab7 and Rab9 coated late endosomes. The Endosomal Sorting Complex (ESCRT) recognizes ubiquitinated proteins and routes them for degradation. Rab GTPases such as Rab3, Rab10 and Rab27 play critical role in the exocytosis/secretory pathway, while Rab1 and 2 are necessary for ER-Golgi transport. Receptor ligand complexes are differentially sensitive to pH, a fact that is utilized by the vesicular trafficking machinery to uncouple the signalosome.

Figure 2. GTP Exchange and Membrane Association Cycles

The newly translated GDP bound Rab in the ER is recognized by REP, and presented to GTT enzyme for prenylation. In many cases, following prenylation, a GDP dissociation inhibitor (GDI) associates with the prenylation group, allowing the Rab to remain in the cytosol, prior to being translocated to the correct endosomal compartment. At this compartment, GDI is removed by GDF allowing a guanine exchange factor (GEF) to facilitate GDP-GTP exchange. The GTP bound Rab can now interact with its effectors and perform various trafficking functions. The membrane associated active GTP Rab is inactivated by GTPase activating proteins (GAPs), thus returning back to the inactive GDP bound state. In some cases, the GDI extracts the GDP bound Rab back into the cytosol, allowing the process to reinitiate.