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Review
. 2021 Jan;288(1):36-55.
doi: 10.1111/febs.15453. Epub 2020 Jul 1.

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

Yuta Homma  1 , Shu Hiragi  1 , Mitsunori Fukuda  1
Affiliations
Review

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

Yuta Homma et al. FEBS J. 2021 Jan.

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.

Keywords: GAP; GEF; Rab small GTPases; effector; knockout; membrane traffic; organelle; post-translational modification.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
The Rab GTPase cycle. Rab GTPases are activated (GTP‐loaded) by guanine nucleotide exchange factors (GEFs) and inactivated (GDP‐loaded) by GTPase‐activating proteins (GAPs). Inactive Rabs bind to GDP dissociation inhibitor (GDI) and are retained in the cytosol [136]. GDI is thought to be dissociated by GDI displacement factor (GDF) [137], but whether this mechanism is applicable to all Rabs remains unclear. Active Rabs are associated with intracellular membranes and recruit specific effector proteins that regulate various steps of membrane trafficking, including budding, transport, tethering, and fusion of vesicles and organelles. Post‐translational modifications (PTMs), such as phosphorylation, of Rabs are thought to regulate their interaction with GDI, GEFs/GAPs, and effectors [138].
Fig. 2
Fig. 2
Phylogenetic analysis of Rabs. Amino acid sequences of the full length (A) or the switch II region (B) of human Rabs have been aligned using the clustalw software program (version 2.1; available at http://clustalw.ddbj.nig.ac.jp/top‐e.html) set at the default parameters and their phylogenetic tree was drawn by the neighbor‐joining method. All Rab sequences used for the phylogenetic analysis were obtained from the NCBI database (see also Figs S1 and S2). Note that the classifications of subfamilies are similar to each other and to the classification based on the full‐length sequences of more than 7600 Rabs from various species [8]. The Rab subfamily members that have been conserved from budding yeasts to humans are enclosed in boxes composed of dashed blue lines. (A) includes budding yeast (Sc) Ypts, Caenorhabditis elegans (Ce) Rabs, and Drosophila melanogaster (Dm) Rabs that are also conserved in humans. Human‐ or primate‐specific Rabs, that is, Rab6C, Rab41/6D, Rab40A, and Rab40AL, have been excluded from this figure.
Fig. 3
Fig. 3
Typical Rabs and Rab‐related proteins. A comparison between typical Rabs (mouse Rab1A and Rab8A) and Rab‐related proteins (mouse Rab44, Rab45, and Rabl2) and their domain architecture are shown. The numbers in parentheses are the protein ID numbers of the respective proteins in the NCBI. Rab44 and Rab45 have long N‐terminal regions containing EF‐hand and coiled‐coil (CC) domains, in addition to their C‐terminal Rab‐like GTPase domains. Rabl2, an example of ‘Rab‐like’ proteins, has a Rab‐like GTPase domain but lacks a C‐terminal prenylation site (indicated by the pink lines), which is required for membrane insertion.
Fig. 4
Fig. 4
New mechanistic models of Rab‐mediated membrane tethering. (A) Podocalyxin (PODXL)‐containing vesicles are directly captured by Rab35 on the target membrane [105]. (B) Binding of EEA1 to Rab5 enables a conformational change in EEA1, which generates the pulling force that brings two endosomes together [106]. (C) Vesicle tethering can be induced by homo‐ and hetero‐typic interactions of Rabs in the absence of any effectors in vitro [109]. See the text for details.
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