Consequences of Rab GTPase dysfunction in genetic or acquired human diseases

Abstract

Rab GTPases are important regulators of intracellular membrane trafficking in eukaryotes. Both activating and inactivating mutations in Rab genes have been identified and implicated in human diseases ranging from neurological disorders to cancer. In addition, altered Rab expression is often associated with disease prognosis. As such, the study of diseases associated with Rabs or Rab-interacting proteins has shed light on the important role of intracellular membrane trafficking in disease etiology. In this review, we cover recent advances in the field with an emphasis on cellular mechanisms.

Keywords: GTPase; Rab; cancer; disease; endocytosis; exocytosis; membrane trafficking; vesicular transport.

Figure 1.

Subcellular localization of mammalian Rab GTPases and disease implications. Each Rab specifically targets and localizes to a membrane compartment along the exocytic and endocytic pathways in the cell as indicated. At steady state, each Rab may be found on multiple related organelles, based on Table 1 and references therein. The association of Rab31 with exocrine granules is based on our unpublished immunohistochemistry data showing Rab31 localization to mucin granules of goblet cells in human and mouse intestinal epithelium. Early endosomes, recycling endosomes and secretory vesicles represent heterogeneous populations of vesicles, and the associated Rabs do not necessarily co-localize on the same vesicles. Also indicated are examples of diseases associated with several Rabs.

Figure 2.

Rab GTPase cycle, Rab-interacting proteins and disease implications. Each newly synthesized Rab initially binds to REP-1, which recruits the α and β subunits of the Rab GGTase for post-translational isoprenylation. The prenylated Rab remains complexed with REP-1 and is targeted to the membrane where a cognate GEF facilitates the nucleotide exchange of GDP for GTP and thereby activates the Rab. The GTP-bound Rab can interact with multiple effector proteins temporally and spatially to promote vesicle formation, movement and fusion. Each Rab associates with a particular type of vesicles and interacts with a specific set of effectors, e.g. Rab5 associates with early endosomes and one of its effectors is APPL1 for signaling on endosomes while Rab27 associates with melanosomes and its effectors include Melanophilin and Myosin Va for movement on actin. Upon membrane tethering and docking, the Rab reaches the target membrane to facilitate SNARE-mediated membrane fusion after which a cognate GAP facilitates GTP hydrolysis and converts the Rab to inactive GDP-bound conformation. The GDP-bound Rab is extracted by GDI and delivered back to the donor membrane for a new round of action. Several diseases are known to be associated with the regulators and effectors of the Rab GTPase cycle as indicated.