Rab family of small GTPases: an updated view on their regulation and functions

Abstract

The Rab family of small GTPases regulates intracellular membrane trafficking by orchestrating the biogenesis, transport, tethering, and fusion of membrane‐bound organelles and vesicles. Like other small GTPases, Rabs cycle between two states, an active (GTP‐loaded) state and an inactive (GDP‐loaded) state, and their cycling is catalyzed by guanine nucleotide exchange factors (GEFs) and GTPase‐activating proteins (GAPs). Because an active form of each Rab localizes on a specific organelle (or vesicle) and recruits various effector proteins to facilitate each step of membrane trafficking, knowing when and where Rabs are activated and what effectors Rabs recruit is crucial to understand their functions. Since the discovery of Rabs, they have been regarded as one of the central hubs for membrane trafficking, and numerous biochemical and genetic studies have revealed the mechanisms of Rab functions in recent years. The results of these studies have included the identification and characterization of novel GEFs, GAPs, and effectors, as well as post‐translational modifications, for example, phosphorylation, of Rabs. Rab functions beyond the simple effector‐recruiting model are also emerging. Furthermore, the recently developed CRISPR/Cas technology has enabled acceleration of knockout analyses in both animals and cultured cells and revealed previously unknown physiological roles of many Rabs. In this review article, we provide the most up‐to‐date and comprehensive lists of GEFs, GAPs, effectors, and knockout phenotypes of mammalian Rabs and discuss recent findings in regard to their regulation and functions.

A comprehensive analysis of Rab GTPases reveals a role for Rab34 in serum starvation-induced primary ciliogenesis

“…Next, we attempted to identify a specific region(s) of Rab34 that is essential for ciliogenesis by performing mutation and deletion analyses of Rab34-KO cells. In general, Rabs are thought to recognize specific effectors through their switch II region, because mutations of specific amino acids in this region of some Rabs have been shown to abrogate their effector-binding ability (31)(32)(33)(34)(35). Sequence comparisons of the switch II region of mammalian Rabs have revealed that Lys-115 and Cys-116 are specific to Rab34 (and its closest paralog Rab36) (34; Fig.…”

Rab GTPases: Key players in melanosome biogenesis, transport, and transfer

“…The Rab GTPases are master regulators of intracellular membrane traffic in all eukaryotes (from budding yeasts to humans), and approximately 60 different Rab isoforms are present in mammals (reviewed in Homma et al., 2020; Pfeffer, 2017; Zhen & Stenmark, 2015). Like other Ras‐like GTPases, Rabs function as switch proteins that cycle between a GTP‐bound active state and a GDP‐bound inactive state (Figure 1a).…”

RBD11, a bioengineered Rab11-binding module for visualizing and analyzing endogenous Rab11

“…Rab GTPases belong to the Ras superfamily of small GTPases and play important roles in membrane trafficking in eukaryotic cells (reviewed in Hutagalung and Novick, 2011;Zhen and Stenmark, 2015;Pfeffer, 2017;Homma et al, 2020). Like other Ras-like GTPases, Rabs cycle between a GTP-bound active state and a GDP-bound inactive state, and the active Rabs promote various membrane trafficking steps, including vesicle budding, tethering, docking, and fusion, through interaction with their specific effectors.…”