Rab proteins: The key regulators of intracellular vesicle transport

doi:10.1016/j.yexcr.2014.07.027

Experimental Cell Research

Volume 328, Issue 1, 15 October 2014, Pages 1-19

https://doi.org/10.1016/j.yexcr.2014.07.027 Get rights and content

Highlights

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Rab proteins regulate different signalling pathways.
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Deregulation of Rabs is the fundamental causes of a variety of human diseases.
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This paper gives potential directions in developing therapeutic targets.
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This paper also gives ample directions for modulating pathways central to normal physiology.
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These are the huge challenges for drug discovery and delivery in near future.

Abstract

Vesicular/membrane trafficking essentially regulates the compartmentalization and abundance of proteins within the cells and contributes in many signalling pathways. This membrane transport in eukaryotic cells is a complex process regulated by a large and diverse array of proteins. A large group of monomeric small GTPases; the Rabs are essential components of this membrane trafficking route. Most of the Rabs are ubiquitously expressed proteins and have been implicated in vesicle formation, vesicle motility/delivery along cytoskeleton elements and docking/fusion at target membranes through the recruitment of effectors. Functional impairments of Rabs affecting transport pathways manifest different diseases. Rab functions are accompanied by cyclical activation and inactivation of GTP-bound and GDP-bound forms between the cytosol and membranes which is regulated by upstream regulators. Rab proteins are characterized by their distinct sub-cellular localization and regulate a wide variety of endocytic, transcytic and exocytic transport pathways. Mutations of Rabs affect cell growth, motility and other biological processes.

Introduction

For proper function of a cell different compartments need to communicate with each other which are mediated by vesicle transport. For example, secretory proteins synthesized on ER need to be transported to the Golgi-complex, and from Golgi to plasma membrane proteins are also transported by vesicles. Vesicles do not move randomly within cell but in a directional manner. There are key players which mediate intra-cellular vesicle transport. One of the ways through which this is achieved is vesicles those are constantly circulating in a cell. They bud off from one membrane and fuse with another and this is tightly regulated. A multitude of studies have shown that most of the membranous organelles in the cytoplasm are part of a dynamic integrated network in which materials are shuttled between different parts of the cell.

During the last few decades tremendous progress has been made in identifying the molecular machinery that governs and regulates membrane trafficking pathways. Each vesicle transport pathway involves budding of a vesicle from a donor membrane followed by the delivery to the correct acceptor membrane [1]. Although, much has been known about these processes but how a carrier vesicle finds it partner/donor membrane still remains a mystery. The dynamic structures of cytoplasmic coat proteins which cycle on and off membranes involve in cargo selection and mediates vesicle budding [2], [3]. In the next step after budding, vesicles are transported by motor proteins (kinesin, dynein and myosin) along microtubules and actin-cytoskeleton elements toward the acceptor membranes [4], [5]. The next step in vesicle transport is tethering; the initial interaction between donor vesicles with its partner vesicle/acceptor membrane resulting in the formation of membrane fusion mediated by the SNARE complexes (Soluble N-ethylmaleimide sensitive factor attachment protein receptor). Rabs coordinate the vesicle transport events and ensure their precision. Tethering factors interact with Rabs to tether the donor membrane with an appropriate acceptor membrane for fusion [6].

In recent years, enormous progress has been made in understanding the role of Rabs during various steps of membrane trafficking. This review provides an overview over our current knowledge of Rab structure and function, the mechanisms governing their sub-cellular localization, their regulation through signalling pathways, their key roles in disease progression, and potential directions for future research.

Section snippets

Overview over Rab family members

Rab proteins are small (21–25 kDa) monomeric GTPases/GTP-binding proteins, and form the largest branch of Ras superfamily. They are evolutionary conserved and found in organisms ranging from yeast to humans, and have been implicated in various cellular functions including growth, protein trafficking, transmembrane signal transduction, targeting and fusion of membrane bound organelles [7], [8]. So far, 70 different Rab proteins in Homo sapiens [8], [9], [10], 11 in Saccharomyces cerevisiae [11],

Rab protein structure

High resolution structural information obtained from X-ray crystallography for different Rabs is presently available [18]. Rab proteins (range between 21 and 25 kDa) consist of several highly conserved regions, which are also found in other members of the Ras superfamily. The well known guanine nucleotide-binding motifs are shared with other GTPases such as elongation factor-Tu, Ras, and trimeric G proteins. In addition several other short sequence motifs are shared exclusively among Rab

Subcellular localization of Rab proteins

Membrane transport in eukaryotic cells is a complex process regulated by a large and diverse array of proteins. The Rab family of small GTPases, comprising approximately 70 members, is the master regulators of intracellular vesicle transport. Each Rab protein is localized to the cytoplasmic surface of a distinct membrane bound organelle [23], [24], [25] and appears to control a specific membrane transport pathway. Individual Rab GTPases have been implicated in regulating the budding, movement,

Rab domain

The different biochemical reactions regulated by Rab proteins raise the concept of domain structure of Rab proteins. The early endosomes (EEs) and the REs have been implicated in recycling of membranes and receptors to the plasma membrane. The distinction between EEs and REs is mainly based on the flow of cargo molecules as well as the spatial distribution of these membranes within the cell. The membrane organization of the recycling pathway is compartmentalized by different domains. These

Rab proteins in the endocytic pathway

Endocytic pathway, the process of uptake of macromolecules by eukaryotic cells through invaginations which bud off from plasma membranes, is required for transport and recycling of proteins. Several Rab proteins are localized to the endocytic pathway in mammalian cells and most of them have been functionally characterized. Recent understanding of Rab proteins that regulate distinct endocytic pathways is presented in Table 1. The endocytic pathway regulates recycling and degradation of

Rab proteins in the transcytic pathway

Transcytosis is a process by which various macromolecular cargos are transported from one side of a cell to the other within a membrane bounded carrier(s). This strategy is used by multi-cellular organisms to selectively move materials between two different environments. In polarized cells (having apical–basal polarity), the endocytic and transcytic pathways share some features those are common with non-polarized cells (without apico-basal polarity). The apical recycling endosome is a

Rab proteins in the exocytic pathway

Exocytic pathway engages the regulated secretion of newly/biosynthetic proteins. Individual Rab proteins govern discrete endocytic and exocytic transport steps [24]. Along the exocytic pathway, ER-to-Golgi transport is regulated by two Rab proteins, Rab1 and Rab2, and intra-Golgi transport depends on the action of Rab6 [92], while transport from the TGN to the cell surface requires Rab8 and Rab11 [38], [54] (Table 1). Rab33 was found to localize at median Golgi and mediates transport of

Rab protein cycle: activation/inactivation and translocation

Rab proteins cycle between the GDP-bound inactive and GTP-bound active forms between the cytosol and membranes. These cyclical activation, inactivation and translocation are regulated by at least three types of regulators: Guanine Nucleotide Exchange Factors (GEPs), GTPase Activating Proteins (GAPs) and GDP Dissociation Inhibitors (GDIs) [100]. After synthesis, Rab proteins are post-translationally modified by lipids that involve the attachment of a geranylgeranyl (20-carbon) group at the

Upstream regulators of Rab

The Rab GTPases function primarily by cycling between the active, GTP-bound membrane and inactive, GDP-bound cytosolic forms, which are orchestrated by three types of upstream regulators, viz., Guanine Nucleotide Exchange Factors (GEFs), GTPase Activating Proteins (GAPs), GDP-Dissociation Inhibitors (GDIs). The overall structural conformations of GDP-bound and GTP-bound form of Ypt/Rabs are quite similar to that of Ras [106].

Downstream effectors of Rab

Rab proteins regulate their particular pathways by interacting with various effector proteins. Rab proteins, like all the GTPases of the Ras family, function as molecular switchs. In the active GTP-bound form Rab protein recruits soluble factors to relay the GTPase signal to downstream effector system/proteins, which respond to a specific Rab and mediates at least one element of the downstream effects. Effectors are defined as proteins which have ability to bind to a specific Rab, selectively

Functions of Rab proteins

A wealth of genetic and biochemical studies have indicated that Rab GTPases function as master regulators of specific intracellular trafficking steps. Rab proteins use the guanine nucleotide-dependent switch mechanism common to the superfamily to regulate each of the four major steps in membrane traffic: vesicle formation/budding, vesicle motility/delivery, vesicle tethering, and fusion of the vesicle membrane with that of the target compartment (Fig. 3). These different steps are carried out

Rab GTPases and signalling pathways

Developmental signalling pathways in multi-cellular organisms are regulated by the endocytic and exocytic trafficking of receptors and their ligands [161], [162]. Rab proteins have been found to present downstream of different signalling pathways, and may impact gene expression and growth control. For example, Rab5 has been involved in EGF signalling pathway and supposed to restore APPL1 and APPL2, which reside on endosomes promoting on nuclear translocation to change gene expression [163].

Rab dysfunction and diseases

Membrane and/or protein trafficking in the secretory and endocytic pathways are mediated by vesicular transport. Recent studies on the Rab GTPases; the key regulators of vesicular transport have linked Rab dysfunction to human diseases. These are summarized below.

Conclusion

Recent studies have shown that more than 10% of the human genome has been implicated in regulating membrane/protein transport pathways. Research discovered hundreds of diseases those are caused directly or indirectly by defects in sequence, expression and the regulation of membrane trafficking proteins [221]. Rab GTPases act as master regulators of vesicular membrane transport on both the exocytic and endocytic, and transcytic pathways. Alterations in endocytic and exocytic Rab protein

Acknowledgment

We would like to thank the reviewers for constructive feedback.

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Review ArticleRab proteins: The key regulators of intracellular vesicle transport

Highlights

Abstract

Introduction

Section snippets

Overview over Rab family members

Rab protein structure

Subcellular localization of Rab proteins

Rab domain

Rab proteins in the endocytic pathway

Rab proteins in the transcytic pathway

Rab proteins in the exocytic pathway

Rab protein cycle: activation/inactivation and translocation

Upstream regulators of Rab

Downstream effectors of Rab

Functions of Rab proteins

Rab GTPases and signalling pathways

Rab dysfunction and diseases

Conclusion

Acknowledgment

Cell

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Curr. Biol.

Curr. Opin. Cell Biol.

J. Mol. Biol.

Trends Biochem. Sci.

Exp. Parasitol.

Cell

FEBS Lett.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Methods Enzymol.

J. Biol. Chem.

FEBS Lett.

Cell

J. Biol. Chem.

Cell

FEBS Lett.

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

Methods Enzymol.

Cell

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Cell

Cell

Curr. Biol.

J. Biol. Chem.

Cell

J. Biol. Chem.

Curr. Biol.

Dev. Cell

J. Biol. Chem.

Coat proteins: shaping membrane transport

Nat. Rev. Mol. Cell Biol.

SNAP receptors implicated in vesicle targeting and fusion

Nature

Human Ras superfamily proteins and related GTPases

Sci. STKE

Rab proteins as membrane organizers

Nat. Rev. Mol. Cell Biol.

Analysis of the small GTPase gene superfamily of Arabidopsis

Plant Physiol.

Thirty-One flavors of Drosophila Rab proteins

Genetics

A yeast gene encoding a protein homologous to the human c-has/bas proto-oncogene product

Nature

Four additional members of the Ras gene superfamily isolated by an oligonucleotide strategy: molecular cloning of YPT-related cDNAs from a rat brain library

Proc. Natl. Acad. Sci. USA

Structural basis of activation and GTP hydrolysis in Rab proteins

Structure

Conformationally variable Rab protein surface regions mapped by limited proteolysis and homology modelling

Biochem. J.

Interactions of three domains distinguishing the Ras-related GTP-binding proteins Ypt1 and Sec4

Nature

Distinct structural elements of Rab5 define its functional specificity

EMBO J.

The role of GTP-binding proteins in transport along the exocytic pathway

Review Article
Rab proteins: The key regulators of intracellular vesicle transport