Rab proteins: the key regulators of intracellular vesicle transport.

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Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/yexcr

Review Article

Rab proteins: The key regulators of intracellular vesicle transport Tanmay Bhuina, Jagat K. Royb,n a

Cell and Developmental Biology Unit, Department of Zoology, The University of Burdwan, Golapbag 713104, India Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi 221005, India

b

article information

abstract

Article Chronology:

Vesicular/membrane trafficking essentially regulates the compartmentalization and abundance of

Received 11 April 2014

proteins within the cells and contributes in many signalling pathways. This membrane transport

Received in revised form

in eukaryotic cells is a complex process regulated by a large and diverse array of proteins. A large

6 July 2014

group of monomeric small GTPases; the Rabs are essential components of this membrane

Accepted 23 July 2014

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

Keywords:

target membranes through the recruitment of effectors. Functional impairments of Rabs affecting

Eukaryotic cells

transport pathways manifest different diseases. Rab functions are accompanied by cyclical

Membrane trafficking

activation and inactivation of GTP-bound and GDP-bound forms between the cytosol and

Cyclical activation

membranes which is regulated by upstream regulators. Rab proteins are characterized by their

Cell growth

distinct sub-cellular localization and regulate a wide variety of endocytic, transcytic and exocytic

Transport pathways

transport pathways. Mutations of Rabs affect cell growth, motility and other biological processes. & 2014 Published by Elsevier Inc.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . 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 Upstream regulators of Rab . . . . . . . . . . .

............... ............... ............... ............... ............... ............... ............... ............... and translocation. ...............

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Corresponding author. Fax: þ91 542 236 8457. E-mail address: [email protected] (J.K. Roy).

http://dx.doi.org/10.1016/j.yexcr.2014.07.027 0014-4827/& 2014 Published by Elsevier Inc.

Please cite this article as: T. Bhuin, J.K. Roy, Rab proteins: The key regulators of intracellular vesicle transport, Exp Cell Res (2014), http: //dx.doi.org/10.1016/j.yexcr.2014.07.027

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Guanine Nucleotide Exchange Factors (GEFs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 GTPase Activating Proteins (GAPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 GDP-Dissociation Inhibitors (GDI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 GDP-dissociation factor (GDF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Downstream effectors of Rab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Functions of Rab proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Vesicle formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Vesicle motility/delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Vesicle tethering. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Membrane fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Rab GTPases and signalling pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Rab dysfunction and diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Choroideremia (CHM). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Griscelli syndrome (GS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Carpenter syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Hermansky–Pudlak Syndrome (HPS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Charcot–Marie–Tooth type 2B disease (CMT-2B) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Warburg Micro syndrome (WARBM) and Martsolf syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 X-linked mental retardation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Hereditary Sensory and Autonomic Neuropathy (HSAN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

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.

Overview over Rab family members Rab proteins are small (21–25 kDa) monomeric GTPases/GTPbinding 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 [8–10], 11 in Saccharomyces cerevisiae [11], 29 in Caenorhabditis elegans, 57 in Arabidopsis thaliana [8,12], 90 in Entamoeba histolytica [13] and around 33 in Drosophila melanogaster [14] have been characterized. The first Rab gene was identified in S. cerevisiae and named as Sec4/Ypt (Yeast protein transcript) [15] which encodes a small G protein that is required for vesicle trafficking from the Golgi apparatus to plasma membrane [16]. Rab proteins are the mammalian homologs. The first mammalian


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homolog of this group of protein was cloned in 1987 and termed as Rab (Ras-like in rat brain) [17]. The Rab proteins are associated with the cytoplasmic face on different exocytic and endocytic organelles as well as on transport vesicles that couple these compartments. The conformational change (occurs when GTP is hydrolyzed by Rab proteins to GDP) regulates the way of transport machinery. Mutations affecting GTP binding or hydrolysis often result in the accumulation of vesicles and prevent their correct transport indicating an involvement of Rabs in the docking/fusion event [10].

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 proteins [19,8]. Rab proteins are evolutionarily conserved with 55–75% identity between orthologs from yeast and mammals compared with 40–50% identity between SNARE orthologs. The most divergent regions in Rab proteins are the amino- and the carboxy-terminal regions. The carboxyterminus of Rab proteins contain XXXCC, XXCCX, XCCXX, CCXXX or XXCXC motif, in which the two cysteines are substrate for prenylation. This modification is essential for membrane binding. The carboxy-terminal hypervariable region is required but not sufficient for correct targeting of Rab proteins to their specific locations in the cell [20,21]. Most of the Rab proteins are tightly associated with membranes through the post-translational addition of two geranylgeranyl (20-carbon polyisoprenoid) groups to two cysteines near the COOH terminus, although a few Rab proteins have only one geranylgeranyl group [22]. The tertiary structure of Rab GTPases closely resembles that of other GTPases, with a central barrel composed of a six-stranded β-sheet surrounded by α-helices. Extensive analyses of other GTPases have defined two regions termed switches I and II located near the phosphate region of the bound guanine nucleotide. These regions undergo dramatic conformational change on nucleotide exchange, and are involved in protein–protein contact and account for the nucleotide dependency of most GTPase interactions.

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 [23–25] and appears to control a specific membrane transport pathway. Individual Rab GTPases have been implicated in regulating the budding, movement, and the delivery of transport vesicles along distinct transport routes. They are predominantly localized to the

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membranes of transport vesicles and to their specific target compartments. In the steady state, Rab proteins accumulate at their target compartment and thereby have been used as markers for different organelles [26,27]. Only a minor fraction of each Rab protein is localized to the cytosol where it makes a complex with a protein called Guanine Dissociation Inhibitor (GDI) [28–30]. Most of the Rab proteins are ubiquitous in their expression while some have a more restricted tissue/cell type specific distribution. For example, Rab3A is a member of Rab protein family that is exclusively associated with the synaptic vesicle of neurons [31], Rab17 is expressed in epithelial cells [32], while Rab27a has been found to express predominantly in hemopoietic cell lineage [33] and Rab13 which is closely related to the yeast Sec4 protein is localized in close proximity to the tight junctions of epithelial cells of various origins [34]. Rab18 is associated with lipid droplet to release lipids from lipid droplets in adipocytes and therefore acts as an excellent marker to follow the dynamics of lipid droplets [35] whereas, Rab32, in its GTP-bound active state, is involved for the fission of mitochondria [36]. Rab12 is involved to transport from peripheral region of cell to perinuclear centrosomes to associate with centrosomes and maintains its integrity [37]. The sub-cellular localization of Rab proteins defines the pathway that they regulate [10]. Rab1 and Rab2 are localized at the ER while Rab6 and Rab8 were originally found to regulate the constitutive transport of newly synthesized membrane proteins from the TGN to the plasma membrane [38], but recent studies have indicated that this might not be the case. Instead Rab8 has been proposed to participate in polarized transport of proteins through reorganization of actin and microtubules [39–41]. Rab33 was found to localize at median Golgi and ferries intraGolgi vesicles [42]. Rab4 and Rab15, localized predominantly at the sorting endosomes, regulate the transport of cargo from this compartment to either the degradative or recycling pathways [43–45]. Rab7 is involved in transporting from early endosomes to late endosomes and acts as a marker for late endosomes [46,47]. Rab9 and Rab24 are involved to transport from LEs to the lysosomes [48,49]. Rab15 is also associated with transporting cargoes from apical recycling endosomes (ARE) to basolateral membranes [45]. Basolateral protein transport from median Golgi and TGN is also carried out by Rab8 and Rab10 [50,51]. Localization of Rab17 and Rab25 to apical recycling endosomes (APEs) facilitates transcytic transport to the apical and basolateral plasma membranes [52,32]. Secretory granules and vesicles are transported from TGN to apico-lateral membranes by Rab3, Rab11, Rab26, Rab27, Rab37, and Rab38 [53–58]. Rab22 and Rab31 mediate vesicle trafficking between TGN and early endosomes and vice versa [59,60]. Rab23 localizes to the plasma membranes and early endocytic vesicles and mediates trafficking between them [61]. Rab21 functions in the early endocytic pathways and its dynamics, and mediates integrin endocytosis from focal adhesion site [62,63]. Rab14 mediates trafficking between early endosomes and Golgi [64,65]. Rab34 is involved in the formation of pinosomes and spatial distribution of lysosomes [66,67]. Rab40 is localized at the Golgi apparatus [68]. Rab11 is localized to the recycling endosomes (REs) [27] and the TGN [54], and regulates transport from the early recycling compartments (ERC) to the plasma membrane, or traffic between the TGN and ERC [27,69] (Fig. 1).


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Fig. 1 – Localization of Rab proteins.

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 domains on endosomes consist of multiple combinations of Rab4, Rab5 and Rab11 that are dynamic but do not significantly intermix over time. Three major populations were observed: one that contains only Rab5, a second with Rab4 and Rab5, and a third containing Rab4 and Rab11. These membrane domains display differential pharmacological sensitivity, reflecting their biochemical and functional diversity. The endosomes are organized as a mosaic of different Rab domains created through the recruitment of specific effector proteins, which cooperatively act to generate a restricted environment on the membrane. These distinct membrane domains on endosomes in the recycling pathways were visualized by multicolor imaging of Rab4, Rab5 and Rab11 [70,10]. Protein–lipid interactions become a central factor in the generation of Rab5 domain. The localized synthesis of PtdIns (3) P not only allows the specific recruitment of FYVE effectors in conjugation with Rab5 but also contributes to their clustering. The dynamic properties of a Rab5 domain probably include a spatial and temporal control over PtdIns (3) P synthesis and turnover [71,72,10]. In addition to this, effector cooperativity for protein oligomerization and actin scaffold in stabilizing the local membrane composition of Rab effectors are another factor in the formation of Rab5 domain [73,74]. Finally, the generation and maintenance of Rab5 domain depend on energy upon hydrolysis

of GTP which regulates the kinetics and limits the extension of effector recruitment [10].

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 endocytosed molecules in a step wise manner. Formation of clathrin-coated endocytic vesicles is the first step along the endocytic pathway and subsequently endocytic vesicles become endosomes. The early sorting endosome is a complex and dynamic membrane system in which endocytosed components are sorted to their different destinations [75–77]. Endocytosed components are directed from the early sorting endosome either towards the degradative or into the recycling pathway. The degradative pathway leads to the late endosomes (LEs) and lysosomes where degradation by acid hydrolases occurs [76,77]. Each trafficking step along the endocytic pathway is mediated by a different Rab protein [78,79,27]. As mentioned above Rab5 mediates traffic from the plasma membrane to the early endosomes (EE) and serves as marker for EE [80] while Rab7 is associated with early sorting endosome to degradative compartment and serves as marker for late endosomes [46,47]; Rab4, Rab11 and Rab35 mediate recycling pathway. In particular, Rab4 and Rab35 control the fast recycling from the EEs and REs directly back to the plasma



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Table 1 – Rab proteins in enodocytic, transcytic and exocytic pathways.

Table 1 (continued ) Rab

Rab

Intracellular localization

Function

Rab1 Rab2 Rab3

ER–Golgi intermediate ER–Golgi intermediate TGN-apico-lateral membranes

ER–Golgi trafficking ER–Golgi trafficking Exocytosis of secretory granules and vesicles from TGN to apico-lateral membranes Endocytic recycling to plasma membrane Endocytic internalization and early endosome fusion

Rab4

Rab6 Rab7

Early and recycling endosomes Clathrin coated vesicles and early endosomes Intra-Golgi Late endosomes

Rab8

Median Golgi and TGN

Rab9

Late endosomes

Rab10

Median Golgi and TGN

Rab11

TGN/post-Golgi vesicles and recycling endosomes Peripheral region of cell to perinuclear centrosomes Early endosomes and Golgi Early and recycling endosomes Epithelial specific; apical recycling endosome ER–Golgi intermediate In apical dense tubules, endocytic structures Early endosomes Early endosomes and TGN

Rab5

Rab12

Rab14 Rab15 Rab17

Rab18 Rab20

Rab21 Rab22

Rab23

Plasma membranes and early endocytic vesicles

Rab24

ER/cis-Golgi region and on late endosomal structures Epithelial specific; apical recycling endosome TGN-apico-lateral membranes

Rab25

Rab26

Rab27 Rab31

Do Early endosomes and TGN

Rab33 Rab35 Rab37

Intra-Golgi Recycling endosomes

Intra-Golgi transport Control late endocytic trafficking Basolateral protein transport from median Golgi and TGN Transport from late endsomes to trans-Golgi Basolateral protein transport from median Golgi and TGN Transport from the Golgi, and apical and basolateral endocytic recycling Transport from peripheral region of cell to perinuclear centrosomes Transport between early endosomes and Golgi Inhibitor of endocytic internalization Transport through apical recycling endosomes ER–Golgi trafficking In apical endocytosis/recycling

Endocytic internalization Transport between TGN and early endosomes and vice versa Transport between plasma membranes and early endocytic vesicles Autophagy-related processes

Transport through apical recycling endosomes Exocytosis of secretory granules and vesicles from TGN to apico-lateral membranes Do Transport between TGN and early endosomes and vice versa Intra-Golgi transport Apical endocytic recycling

5

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Rab38 Rab43

Intracellular localization

Function

TGN-apico-lateral membranes

Exocytosis of secretory granules and vesicles from TGN to apico-lateral membranes Do ER–Golgi trafficking

Do ER–Golgi intermediate

membrane [44,81,82], whereas Rab11 controls recycling through the REs [27]. Rab9 is involved in transport from LEs to the TGN [83]. Both Rab5 [80,26] and Rab4 [84] are associated with EEs. In the steady state, these Rab proteins are localized to their target compartments and thereby have been used as markers for the different endocytic compartments. Recently, another Rab protein, the Rab15, was also localized on EEs where it co-localizes with Rab5, Rab4 and Rab11 on pericentriolar REs. Over-expression of Rab15 inhibits fluid phase and receptor-mediated endocytosis without affecting the rate of recycling from early endosomal compartments [45]. In vitro, it inhibits homotypic EE fusion and the inactive mutants affect recycling from the early endosomal compartments suggesting that Rab15 may counteract the reported stimulatory effect of Rab5 on endocytosis.

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 multicellular 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 specialized epithelial organelle similar to REs in non-polarized cells that facilitates polarized recycling and transcytosis [85,86]. Rab11 is associated primarily on apical recycling endosomes of epithelial cells [52,87] and it regulates apical recycling of Hþ/Kþ ATPase in gastric parietal cells [88]. In addition to the ubiquitous Rab GTPases, a set of epithelia-specific Rab proteins, including Rab17, Rab18, Rab20 and Rab25, facilitate endocytic and transcytic transport to the apical and basolateral plasma membranes [52]. Rab17 and Rab25 regulate some aspects of polarized sorting and receptor mediated transcytosis. Rab17 is important for apical recycling and transcytosis to the apical membrane [89]. In one system over-expression of wild type Rab17 inhibited basolateral to apical transcytosis [89] (Table 1) and in other system two mutant forms of Rab17 stimulated this pathway together with the apical recycling pathway. In a similar scenario over-expression of wild type Rab25 in MDCK cells decreased apical recycling and basolateral to apical transcytosis of IgA, while the dominantnegative form of Rab25T26N had no effect on either of these pathways suggesting a negative regulatory role of Rab25 in exit from the RE [52] or its function in retrograde trafficking from REs to the Golgi. If so, the closely related Rab11 and Rab25 GTPases could cooperatively regulate the homeostasis of the REs. Localization of at least three different Rab proteins, Rab11, Rab17 and


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Rab25 to AREs creates the complexity of an endocytic recycling system. In polarized epithelial cells, Rab18 localizes to both apical and basolateral domains [32] suggesting a role in transcytosis similar to Rab17. Localization of Rab20 in apical dense tubules and on endocytic structures underlying the apical plasma membrane suggests that they play a role in apical endocytosis/recycling [90]. Classical recycling assays and photoactivable FGFR4–PA–GFP fusion protein combined with live-cell imaging show that recycling of FGFR4 is dependent on Rab11 indicating its transcytic function in FGFR4 trafficking [91].

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 intraGolgi vesicles [42]. Rab8 was found to be important in the transport of vesicular stomatitis virus (VSV) G protein and Semliki Forest virus spike glycoproteins to the cell surface of polarized and nonpolarized cells, respectively [93,41]. Rab11 has been found on a variety of subcellular membranes. In non-polarized cells Rab11 was found to be associated with both the Golgi and the RE [69,27]. In polarized and regulated secretory cells, Rab11 has been localized to the Golgi as well as a variety of specialized membrane compartments [94,95,87]. The complex localization profiles of Rab11 in diverse cell types have been complicated the assessment of its precise function in intracellular protein/membrane transport. Rab11 has been shown to be associated with post-Golgi vesicles, secretory vesicles [54], and the pericentriolar REs [69,27] along with the AREs in polarized cells [52]. Transfection experiments with CHO or BHK cells indicate that Rab11 regulates transferrin recycling through the pericentriolar endosomal compartment [27,54]. Function of Rab11 in exocytic trafficking has been obtained from its requirement for transport from the TGN to the plasma membrane [40]. In addition to this, it was shown that Rab11 regulates transport from EEs to the TGN [69] suggesting that Rab11 may control the interconnection between the endocytic and secretory pathways. Recently, it has been demonstrated that Rab11 is associated with TGN in embryos, in developing photoreceptor cells, and during male meiosis of Drosophila [96–98] implicating its exocytic function. Rab10 controls the exocytic delivery of basement membrane (BM) proteins to the basal cell surface during development of Drosophila follicle cells [99]. Rab3, Rab11, Rab26, Rab27, Rab37, and Rab38 mediate exocytic transport of secretory granules and vesicles from TGN to apico-lateral membranes [53–58].

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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 carboxylterminal cysteine residues and this modification is crucial for their function. After synthesis, Rab proteins associate with the cytosolic Rab escort protein (REP) and form a stable complex [101]. Then, this complex acts as substrate of Rab-geranylgeranyltransferase (Rab-GGT) and subjected to dual prenylation of C-terminal cysteine motifs. Geranylgeranyl groups make the Rab protein hydrophobic and are essential for reversible membrane association [102,103]. The doubly geranylgeranylated Rab protein is thought to remain associated with REP, that delivers the GTPase to a specific organelle or transport vesicle. The REPassociated Rab GTPases are thought to be in the GDP-bound form, whereas membrane delivery is accompanied by the action of a guanine nucleotide exchange protein (GEP) and the Rab in its GDP-bound form is converted to the GTP-bound state and the dissociation of REP occurs [102]. Membrane-bound Rab GTP is stabilized by the recruitment of cytosolic effector proteins and regulates the activity of a downstream v/t-SNARE complex [73,104]. Upon GTP hydrolysis of the Rab protein, mediated by a GTPase Activating Protein (GAP), the active Rab is converted back to the GDP-bound form. Next, membrane bound Rab GDP is released from the membrane by the GDP Dissociation Inhibitor (GDI) and translocated to the cytosol as a Rab–GDI complex [30] (Fig. 2). GDI has structural similarities with REP and like REP; GDI now helps in initiation of a new cycle by targeting a bound Rab to a specific organelle. Thus GDI plays analogous role of REP in the delivery of newly synthesized Rab to the organelle [105].

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].

Guanine Nucleotide Exchange Factors (GEFs) GEFs act as positive regulators which stimulate the nucleotide exchange activity (stimulation occurs at donor compartment) in achieving the conformational changes seen in GTP-bound and GDP-bound form of Rabs [18,107,108]. Yeast Dss4 and its mammalian counterpart, Mss4, were first isolated and characterized as Rab GEFs [109,110]. Dss4 is active on both Sec4 and Ypt1 and Mss4 is active on a subset of Rab proteins [111].

GTPase Activating Proteins (GAPs)

Rab protein cycle: activation/inactivation and translocation Rab proteins cycle between the GDP-bound inactive and GTPbound active forms between the cytosol and membranes. These cyclical activation, inactivation and translocation are regulated by

GAPs act as negative regulators and function at acceptor membrane of Ypt/Rabs. GTP hydrolysis of the Rab protein is achieved by GTPase Activating Protein (GAP) which converts the active Rab back to the GDP-bound form and its release from the target membrane. This is important for membrane fusion [112,7]. In case



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Fig. 2 – Functional cycle of Rab proteins. Newly synthesized Rab protein associates with REP and GDP to form a stable complex that acts as a substrate for RGGT. After lipid transfer, Rab–GDP–REP complex is delivered to the donor membrane and then REP is dissociated and prenylated Rab is ready to attach to the donor membrane. In the absence of REP or RabGGT, Rab proteins stay on in the cytoplasm as an inactive form. GDF catalyzes the dissociation of GDI from Rab protein. The transfer of Rab proteins between the donor and acceptor membranes is aided by the GDI. RabGDP is activated to RabGTP by a GEF which prevents the association of REP and GDI. In the active state, Rab proteins interact with effectors and tethering complexes that regulate vesicle fusion with the acceptor membrane. RabGTP is hydrolyzed by GAP which converts RabGTP to inactive RabGDP. Then, RabGDP is extracted from donor membrane by GDI which serve to maintain RabGDP in the cytoplasm for delivering it to the next cycle to the acceptor membrane.

of Rab5, biochemical studies indicated that the GTP hydrolysis stimulated by GAP acts as a timer to regulate fusion of clathrincoated vesicles with EE and homotypic fusion between endosomes [113].

GDP-Dissociation Inhibitors (GDI) This binds with membrane bound Rab–GDP and exerts from the membrane to form a Rab–GDP–GDI complex into the cytosol [30] and finally recycled back Rab as Rab–GDP complex at donor membrane.

GDP-dissociation factor (GDF) Membrane-associated GDFs are anticipated to distinguish subsets of Rab proteins. They catalyze the dissociation of GDI from prenylated Rab proteins [114].

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 in its GTP-bound state, and have been identified through a variety of approaches, such as the yeast two-hybrid system, genetic screens and affinity purification [115,116], although there are examples, such as protrudin, that interact preferentially with the GDP-bound form of Rab11 [117]. Different Rab effectors perform during vesicle formation, movement, tethering, and fusion, with each pathway having its own unique set of effectors. The number of identified Rab effector proteins is growing steadily as reviewed in Table 2, yet little is known about how Rabs are localized correctly within cells [118]. Due to the high degree of sequence conservation in Rab proteins, most of the effector proteins have unrelated amino acid sequences. A single Rab protein can interact with multiple effectors as originally discovered for Ras establishing the idea that a given Rab may regulate multiple biochemical reactions at distinct sites in a transport pathway between two organelles as was shown for Rab5 [10]. The first identified effector for a Rab protein was Rabphilin3 [119,120] which interacts with Rab3A in the GTP-bound state and is localized to the membranes of synaptic vesicles and chromaffin granules, and is involved in


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Table 2 – Rab effectors (modified and reviewed by Grosshans et al. [116]). Rab

Effector

Effector function

Effector partners

Rab1

p115

Tethering

Rab3 Rab4 Rab5

Synaptic vesicle fusion Protein sorting and recycling Tethering and fusion

Rab6 Rab7 Rab8

Rabphilin-3, Noc2, RIM1, RIM2 Rabaptin-4, Rabaptin-5, Rabaptin-5β Rabaptin-5, p150, Rabaptin-5β, Vac1, EEA1 (early endosome antigen 1), Rabenosyn-5, phosphoinositide 3-kinase, Vps (Vps-Vacuole protein sorting) 34,45, CORVET (Class C core vacuole/endosome tethering) Rabkinesin6,GAPCenA Rabring, HOPS (Homotypic fusion and protein sorting) complex Rab8IP (IP-interacting protein)

GM130, Giantin, Golgin-84 Rabaptin-5, RIM-BP1 Rabex-5 Rabex-5, Rabphilin3, Syntaxin 13, Syntaxin 16 Microtubules Not identified (NI) NI

Rab9

p40, TIP47 (TIP-Tail interacting protein)

Rab11 Rab13

Rabphilin11, Rab11BP (BP-Binding protein), FIP2, FIP3, FIP4 (FIFP-Family interacting protein), Sec15, RIP11(RIP-Rab interacting protein) Delta-PDE

Rab15 Rab27 Rab33b Rab34

REP15 (REP-Rab escort protein) Melanophilin, Rabphilin-3, Noc2, Granuphilin (SLP4) Rab33b-BP RILP

Sec4p Ypt1p Vps21p/Ypt51

Sec15p (Sec-Secretory protein) Uso1p, Sec34/35p Vac1p

Ypt6p Ypt7p (YptYeast protein transcript) Ypt31/32p

GARP/VFT (Vps52p) Vamp2 (Vamp-vesicle associated membrane protein), Vamp6, HOPS complex Sec2p, Rcy1p

exocytosis [121,122]. More than 20 effectors have been identified for Rab5. The Rab5 effector, Rabaptin-5, is an essential component for EE fusion. The other characterized Rab5 effectors includes phosphatidylinositol-3-OH-kinases [PI(3)-kinases], hVPS34 [123], CORVET and HOPS [124]. Among which hVPS34 regulates recruitment of endosome associated antigen (EEA1) to EEs [123]. EEA1 was recently shown to be another Rab5 effector, and required for homotypic early endosome fusion [125]. In addition to a Rab5 binding domain, EEA1 contains a carboxyl-terminal FYVE finger that is required for EE association as well as for phosphatidylinositol-3-phosphate PI(3)P) binding [126,127]. By using a Rab5 affinity column another Rab5 effector protein, Rabenosyn-5, was identified which is recruited in a PI(3)-kinase dependent way to EEs. Rabenosyn-5 and EEA1 are required for endosome fusion [128]. Recently, CORVET complex has been identified as a Rab5 effector complex in yeast and in metazoan cells, whereas HOPS complex binds efficiently to LE and lysosomes through Rab7 in yeast and in metazoan cells also and therefore acts as an efficient Rab7 effector. CORVET functions in endosome–endosome fusion by binding to Rab5 in its GTP binding form. At the LE, Rab5 is replaced by Rab7, which then interacts with HOPS complex in the fusion process [124].

Vesicle motility Vesicle fusion Stress-activated protein kinase and transport Cargo adaptor, sorting and stimulates fusion Exocytosis, transport and recycling of endosome Extracts Rab13 from membrane Regulate exit from RE Exocytosis and transport Motility of Rab33 vesicles Regulate intracellular localization and morphology of lysosomes Acts as tethering complex Tethering complex TGN to Golgi and Late LE to vacuole transport Tethering complex Tethering and nucleotide exchange Vesicle formation and transport

NI Exocyst complex (Sec13) NI NI NI NI NI

Exocyst complex NI Vps45p, Pep12p NI Vamp3p,Hops complex NI

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 nucleotidedependent 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 by a diverse collection of effector molecules that bind to specific Rabs in their GTP-bound state as described below:

Vesicle formation Rab proteins and their effectors are involved in the formation of transport vesicles (Fig. 3). During transporting vesicle, the correct cargo and the appropriate transport and fusion machinery must be incorporated into the vesicle before scission from the donor membrane. Rab1 regulates COPII mediated trafficking between the ER and Golgi complex as well as recruitment of the tethering



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Fig. 3 – Function of RabGTPases. Vesicle formation—RabGTPases and effectors are engaged in membrane sorting and vesicle formation from the donar membrane. Vesicle motility—in the next step RabGTPases with the help of molecular motors drive the transport vesicle along the cytoskeleton track. Vesicle docking—RabGTPases, associating with tethering factors, help the cargo vesicles for docking in the acceptor membrane. Finally, Rab proteins help to fuse the cargo vesicles with the acceptor membrane.

factor p115 during budding of COPII vesicles, which in turn interact with a complex comprising membrin, rbet1, and syntaxin5 [129]. This complex of SNARE proteins, although not directly interacts with Rab1, is needed for targeting the COPII vesicles to the Golgi complex and their fusion with the Golgi membrane. Possibly the recruitment of this complex onto the forming vesicle already programs it for the next stage in its route. Ypt1p (the yeast homolog of Rab1) is not essential for COPII vesicle formation but is required at the target Golgi membrane [130], suggesting that additional mechanisms are involved in ER to Golgi transport. Rab5 is involved in vesicle budding from the cell surface. A cytosolic Rab5–RabGDI complex has been purified as a critical component for sequestering transferrin receptor into clathrin coated pits in permeabilized cells [131]. An opposing function of a direct interaction between receptors and Rab proteins is suggested by the association of Rab3b in its GTP bound form with the transcytosing polymeric Ig receptor (pIgR) [132]. Dissociation of the complex is brought about by Rab3b–GTP hydrolysis. An insight into how Rab proteins may assist in sequestering cargo molecules into budding vesicles was provided by studies on Rab9. Rab9 is predominantly localized on LEs and like its effector TIP47 is required for transport of mannose 6phosphate receptors from endosomes to the TGN [133,134]. The cooperative action of the three components forming the complex is required for transport from endosomes to the TGN. Interestingly, Rab9 enhanced binding of TIP47 to CI-MPR, while, vice versa, CI-MPR increased the affinity of Rab9 to TIP47, suggesting that Rab9 likely enhanced TIP47 recruitment to endosomes and cargo capture.

Vesicle motility/delivery Vesicles are often actively transported (Fig. 3) through the cytoplasm to their target membrane either by actin-dependent (myosins) or microtubule-dependent motors (kinesins or dyneins) [135]. A number of studies have uncovered the involvement of Rabs and their effectors in the regulation of this transport step. The first indication that Rab proteins are involved in vesicle motility came from Novick's lab, who found that MYO-V interacted genetically with Sec4 [136] and with a subset of late acting Sec genes that also genetically interact with Sec4. Subsequently, others reported that the product Myo2p co-localized as well as co-immunoprecipitated with Sec4p [137,138] supporting the proposal that activated GTP-Sec4p promotes myosin-dependent movement of secretory vesicles along actin cables. As actincytoskeleton provides major route for vesicular transport in yeast, these observations might explain why secretory vesicles in yeast are transported along actin cables to the growing bud. However, it is not yet clear how Sec4-containing vesicles are attached to the myosin motor. In some cases, it appears that a motor protein is directly attached to a Rab, for example yeast two-hybrid screen suggested that active Rab6 binds the microtubule motor Rabkinesin-6 and could thereby promote the delivery of vesicles from the Golgi to the ER [139]. More typically, Rabs interact with motors via an intermediary protein. Perhaps the best-studied example is the recruitment of myosin-Va, to melanosomes by Rab27a. Rab27a has been found to localize pigment-containing melanosome granules and is essential for their retention at the cell periphery of melanocytes [140]. The Rab27a effector


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melanophilin links Rab27a positive melanosomes to the actin motor myosin-Va [141,142]. Without myosin-Va-dependent capture of these organelles on actin-filaments, melanosomes are not retained in the cell periphery and, subsequently, cannot be transferred to neighboring keratinocytes [143]. As a result, mouse mutants of Rab27, its effector melanophilin, or myosin-Va display a pigmentary dilution of their skin hence their names, ashen, leaden, and dilute mice, respectively [144]. Genetic alterations of human Rab27a lead to Griscelli syndrome that is manifested as light skin and hair color. Additionally, Griscelli patients display various immunodeficiencies because Rab27a and its effectors are also required for various exocytic transport events [145].

Vesicle tethering The next step of membrane transport is the tethering of transport vesicles (Fig. 3); the initial contact between a transport vesicle and the target compartment with which it fuses brings the vesicle and target membrane into close proximity [146–148]. Vesicle tethering has been described as conserved mechanisms and several lines of evidences have indicated that Rab effectors like Rabaptin-5, early endosome antigen1 (EEA1), Rabphilin-3A and Rim act as tethering factor. Though SNARE complexes act as mediators of membrane fusion, but several lines of experimental evidences indicated that the SNARE complex has not been implicated in tethering [149,10]. Tethering factors can be divided into two groups: long coiled-coil proteins (p115, EEA and Golgins) and large multi-subunit complexes (exocyst complex, TRAPP-I and TRAPP-II, the conserved oligomeric Golgi complex). The interaction of the vesicle-associated protein p115 with a Golgi-residing GM130 and GRASP65-containing complex is thought to tether ERderived vesicles to the Golgi [150]. Interestingly, tethers, vesicleassociated p115, with the GM130 and GRASP65 complex at the Golgi, have been shown to be effectors of Rab1 [151]. The role of Rab1 on the Golgi may be in the regulation of assembly and/or activity of the GM130 and GRASP65 complex [152]. The exocyst was the first large, multisubunit tethering complex originally identified as a Sec4 effector in yeast and latter Sec6/8 complex in mammalian system effector [153,154]. One of its subunits, Sec15p, directly interacts with the Rab/Sec4p in its GTP-bound form in yeast [155]. Sec8p, another exocyst subunit, was recently found to coimmunoprecipitate with Sec4p, indicating that the entire exocyst complex acts downstream of Sec4p [156]. One more subunit of exocyst complex, Sec15p in mammals and Drosophila, has been identified as a Rab11 effector, indicating a conserved interaction between Rabs and the exocyst complex [157,158].

Membrane fusion Rabs have also been implicated in vesicle fusion, together with SNAREs (Fig. 3). Vesicle associated SNAREs (v-SNAREs) and SNAREs at the target membrane (t-SNAREs) form trans-SNARE complexes resulting in the formation of fusion pore and final fusion of vesicle and organelle membranes [159]. Although it is not clear how tethering of two membranes promotes their fusion, it could be speculated that alternatively, or simultaneously, oligomeric tethering complexes after removing inhibitory proteins from t-SNAREs allow them in pairing with trans-SNARE complexes. Regulation of SNARE function mediated by Rabs as exemplified by interaction of Rab5 effector and coiled-coil

] (]]]]) ]]]–]]]

tethering factor, EEA1, with the t-SNARE, syntaxin-13, is essential for homotypic EE fusion [73]. N-ethylmaleimide-sensitive factor (NSF), an ATPase that disassembles preformed cis-SNARE complexes before tethering, is required for Rab effector–SNARE interaction and effector complex formation [73,160]. In mammals, the association of Rabex5 and Rabaptin5 complex with the tethering factor EEA1 on endosomal membranes also depends on NSF [73]. These actions of NSF may couple cis-SNARE complex disassembly to later stages of the reaction, tethering, and transSNARE pairing. In summary, function of Rab is essential for fusion to the target membrane as indicated by the finding that SNARE interacting proteins are Rab effectors. However, the exact functions of these interactions are still unknown. Possibly, the coordination of Rab activity at both vesicle budding and fusion sites would provide a feedback loop to ensure that the amount of vesicles which is consumed through fusion with a target organelle is balanced by the number of vesicles that is formed from the donor organelle.

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]. Rab25 and Rab11a have been implicated in EGFR and TGFβ signaling, and trafficking for the regulation of cell proliferation and differentiation [164,165]. Other Rab family members (Rab5, Rab8, and Rab24) signal to the nucleus to work in collaboration with Ran GTPase, and control nucleocytoplasmic shuttle in changing cell growth and differentiation [166]. In mouse Rab23 acts as a negative regulator of sonic hedgehog signalling pathway [167,61]. In neurons, retrograde transport of the nerve growth factor (NGF) signalling complexes via endosomes is indispensable for feasibility of axon through ERK signalling pathways and transcriptional regulation. This pathway is negatively keeping up by the Rab5 effector huntingtin, which increases endosome links to the peripheral actin network and reduces nuclear signaling [168]. Antiapoptotic effects of Rab25 naked Bcl-2 and phosphoinositide-3-kinase pathways which regulates cell survival [169,170]. Imposed expression of Rab25 in ovarian cancer cells decreases the levels of BAX and BAK proteins in apoptotic signalling pathways and increases AKT phosphorylation [171]. Rab40 is required for normal gastrulation in Xenopus and regulates the membrane localization of Dishevelled (Dsh), a key signalling molecule in the Wnt pathway, through Rap2 and its effector Misshapen/Nck-interacting kinase (XMINK) indicating a role for Rab40 in the regulation of the noncanonical Wnt pathway [68]. Rab22 regulates nerve growth factor (NGF) signallingdependent neurite outgrowth and gene expression in PC12 cells by sorting NGF and the activated/phosphorylated receptor (pTrkA) into signalling endosomes to continue signal transduction in the cell [172]. Rab11 has been found to regulate different signalling pathways during Drosophila development. One of the Rab11 allele, Rab11EP(3)3017, showed dorsal closure defects and puckering in



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homozygous mutant Drosophila embryos [173], a typical phenotype similar to DJNK mutants. Genetic interaction study between Rab11 and candidates of the JNK signalling pathway was carried out during Drosophila eye development. A down-regulation of JNK signalling rescued the phenotype in Rab11 mutant eyes significantly while over-expression of JNK in the eyes using UAS-eiger, UAS-dtak1 or EP(2)0578, resulted in enhancement of the eye phenotype indicating a link between Rab11 and the JNK signalling pathway [174]. Rab11 has also been shown to regulate JNK and Raf/MAPK–ERK signalling pathways during Drosophila wing development. Immunofluorescence and immunohistochemical analyses showed that over-expression of Rab11 in mutant wing imaginal disc cells triggers the induction of apoptosis and activation of JNK and ERK. Further, using a genetic approach it has been shown that Rab11 interacts with the components of these pathways during Drosophila wing development. In addition to this, in Rab11 mutant wing imaginal discs JNK activity was monitored using puc(E)69, a P-lacZ enhancer-trap line inserted in puckered (puc). A strong induction of puc in Rab11 mutant wing imaginal disc cells provided a strong support that Rab11 regulates the JNK signalling pathway during Drosophila wing development [175].

Rab dysfunction and diseases Membrane and/or protein trafficking in the secretory and endocytic pathways are mediated by vesicular transport. Recent Q2 studies on the Rab GTPases have shown that the key regulators of vesicular transport have linked Rab dysfunction to human diseases. These are summarized below.

Choroideremia (CHM) This is an X-linked form of retinal degeneration characterized by the progressive night blindness and loss of peripheral vision results from the degeneration of retinal pigment epithelium (RPE) and the two adjacent cell layers, choroid and photoreceptor cells in the retina [176]. The gene responsible for CHM is localized to chromosomal band Xq21, and named as CHM [177] which encodes REP-1 [178]. All known mutations of CHM gene results loss of CHM/REP-1 protein function. A cell contains two REP proteins REP-1 and REP-2; those are bound to the newly synthesized Rab proteins to deliver Rabs to the enzyme Rab geranylgeranyl transferase (RGGT) for prenylation. In choroideremia lymphoblasts, Rab27a protein found to be unprenylated and is expressed in RPE and the two retinal cell layers that degenerate earliest in CHM suggesting that unprenylated and thus nonfunctional Rab27a is one of the causes of CHM [179].

Griscelli syndrome (GS) This is a rare autosomal recessive disorder characterized by the partial cutaneous albinism due to defects of melanosome transport and immunodeficiency due to the failure of cytotoxic T lymphocytes to discharge contents of their lytic granules. Rab27a is expressed in melanosomes of the melanocytes to transport of these to the periphery of melanocytes. Most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (haemophagocytic syndrome; HS). These results suggest that HS in patients with Griscelli syndrome is caused by the

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absence of Rab27a function due to mutation. Rab27a appears to be a key effector of cytotoxic granule exocytosis, which is important for immune homeostasis [180–183].

Carpenter syndrome This is an autosomal recessive [184] congenital disorder characterized by the premature closing of skull bones (craniosynostosis), craniofacial abnormalities, obesity, syndactyly, abnormalities of the fingers and toes, heart defects, growth retardation and other developmental problems. This is caused by mutation of Rab23 gene on human chromosome 6. Rab23 protein controls developmental signalling pathway called the hedgehog pathway which is vital in cell proliferation, cell specialization, and the normal patterning of body parts. Due to the mutation of Rab23 gene anomalies in normal shaping of the aforesaid body parts occur [185].

Hermansky–Pudlak Syndrome (HPS) HPS, a rare autosomal recessive genetically heterogeneous human disorder, characterized by partial albinism, prolonged bleeding, and these are caused due to the defects in biogenesis of melanosomes and platelet dense granules, frequently referred to as lysosome-related organelles. Several genes have been implicated in HPS patients; whose products either of unknown function or established players in vesicular transport [186,187]. Studies indicated that deficiency of Rab(s) prenylation results in the HPS phenotype. Consistent with this, a subset of Rabs accumulate unprenylated in cytosol including Rab27a in this disease. This is caused by the mutation in RGGT (RGGT-α subunit) gene which fails the prenylation of Rab27a and thus accumulates unprenylated [179]. Recently, genes mutated in HPS encode subunits of the biogenesis of lysosome-related organelles complexes (BLOCs). BLOC-1 and BLOC-2, along with the AP-3 clathrin adaptor complex, act on EEs to sort components required for melanin formation and melanosome biogenesis. Melanosome biogenesis and transport of enzymes occupied by pigmentation require specific Rab GTPases, like; Rab32 and Rab38. Silencing of the BLOC-3 subunits Hps1 and Hps4, Rab32 and Rab38 Guanine Nucleotide Exchange Factor (GEF), results in the mislocalization of Rab32 and Rab38 and decrease in pigmentation. BLOC-3 can promote specific membrane recruitment of Rab32/38 suggesting a novel Rab GEF family with a specific function in the biogenesis of lysosome-related organelles [188].

Charcot–Marie–Tooth type 2B disease (CMT-2B) This is an autosomal dominant heterogeneous form of peripheral neuropathy characterized by axonal degeneration; prominent sensory loss, muscle weakness and atrophy of lower legs, high frequency of ulcers and infections [189,190]. This is caused by four separate missense mutations in Rab7 gene [191].

Warburg Micro syndrome (WARBM) and Martsolf syndrome This is a rare autosomal recessive genetic human disorder characterized by the abnormalities in eye, brain and endocrine system. Patients are characterized by severe mental retardation,


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microcephaly, and hypoplasia of the corpus callosum, microgenitalia and typical ocular findings, like microphthalmia, microcornea, congenital cataract, and optic atrophy. The patients also have dysmorphic features, such as beaked nose with a prominent nasal root, large anteverted ears, hypertrichosis, micrognathia, and highly arched palate. Seizures and/or limb contractures may develop in some patients and delayed puberty is also usually observed [192]. This disease is caused by homozygous mutation in the Rab3GAP gene. Warburg Micro syndrome-1 (WARBM-1) is caused by mutation in the Rab3GAP1 gene on human chromosome 2. Warburg Micro syndrome-2 (WARBM2) is caused by mutation in the Rab3GAP2 gene on human chromosome 1. Warburg Micro syndrome-3 (WARBM3) is caused by mutation in the Rab18 gene on human chromosome 10. Martsolf syndrome, a clinically overlapping but milder autosomal recessive disorder, is caused by autosomal recessive mutation in the Rab3GAP2 gene [193–196]. Rab3GAP gene product has been implicated in the regulation of neurodevelopmental processes viz; proliferation, migration and differentiation before synapse formation, nonsynaptic vesicular release of neurotransmitters, and regulated exocytosis of hormones. Patients of microsyndrome harbor mutaQ3 tions in the gene coding for the catalytic region of this protein. It is assumed that mutations lead to defects in the vesicular transport routes, and exocytosis of neurotransmitters and hormones [192].

X-linked mental retardation This is characterized by neural hyper-excitability and epileptic seizure caused by the mutations in Rab GDP-Dissociation Inhibitor gene α (RabGDI-α). One of these mutations result reduced GDI binding and recycling of Rab3a. RabGDI-α is one of the three known mammalian RabGDI isoforms, which is predominantly expressed in the brain. Rab3a is involved in the regulation of synaptic vesicle recycling and neurotransmitter release in neuronal cells [197]. Recently, mutations in the Small GTPase gene Rab38b have been identified for X-linked mental retardation associated with autism, epilepsy, and macrocephaly suggesting vital role of vesicular trafficking in the development of neurons [198].

Hereditary Sensory and Autonomic Neuropathy (HSAN) This is an autosomal recessive disease, more common in Jewish patients, affecting the autonomous nervous system, characterized by the loss of pain and temperature sensation, alacrima, excessive sweating and absence of fungiform tongue papillae. The HSAN type 1 subtype is associated with mutations in Rab7 [199,200] and in serine palmitoyl transferase, a rate-restrictive step in sphingolipid synthesis. Rab7 transports the synthesized lipid from EEs to LEs and LEs to lysosomes and mutations in the largely expressed serine palmitoyl transferase result in selective disorders of cells in the autonomous nervous system [201,202].

Neurodegenerative diseases Rab5 in neuronal cells is crucial for synaptic plasticity and its protection, and plays a vital role in AMPA (alpha-amino-3hydroxy-5-methylisoxazole-4-propionic acid); the glutamate

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receptor internalization and neurotransmission. Rab5 defects are observed in different neurodegenerative disorders viz; in autosomal recessive motor neuron disease caused by loss of function of Alsin [Alsin is produced by ALS2 gene (Amyotrophic lateral sclerosis 2)], which acts as a GEF for Rab5 [203]. Interaction of Rab5 with Alsin alters insulin-like growth factor 1 and other signalling factors leading to the development of ALS disorder [204]. Huntingtin (Htt) and Huntingtin-associated protein (HAP40) were identified as Rab5 effectors that regulate endosome motility. HAP40 over-expression results a strong reduction of EEs motility through their displacement from microtubules and special association with actin filaments. Up-regulation of endogenous HAP40 was found in fibroblasts and brain tissue of Huntington's disease patients which reduces mobility of Rab5 endosomes and derails endosomal transport, contributing to neurodegeneration [205]. Mutations in the α-synuclein gene result in the disruption of ER–Golgi transport during early stages of Parkinson disease. Rab1 over-expression reduces the toxic effects of α-synuclein and thereby protecting neurodegeneration [206,207]. Dysfunction of endocytic system occurs in Alzheimer's disease (AD). The genes regulating early and late endosomes are selectively up-regulated and elevation of rab4, rab5, and rab7 expression is consistent in AD supporting that endosomal pathology accelerates endocytosis and endosome recycling, which may promote aberrant endosomal signalling and neurodegeneration throughout the progression of AD [208]. Genetic studies have demonstrated that β-amyloid protein (Aβ) plays a pivotal role in AD pathogenesis but how aging contributes to the commencement of AD remains unclear. Cytoplasmic dynein a microtubule-based motor protein mediates minus end-directed vesicle transport via interactions with another microtubule-associated protein dynactin. Normal aging attenuates the interaction between dynein–dynactin complexes in monkey brain and dynein dysfunction reproduces agedependent endocytic disturbances resulting in intracellular Aβ accumulation. Dynein dysfunction disrupts not only retrograde transport of neurotrophic receptors but also anterograde transport of synaptic vesicles, which occurs concomitantly with an increase in Rab3 GTPase levels. Additionally, synaptic vesicle docking was perturbed via enhanced endocytosis. Dynein dysfunction also induced neuritic swelling, which is accompanied by a significant accumulation of neurofilaments. Dynein dysfunction-related disturbances are associated with aging in monkey brains and age-dependent endocytic disturbances precede Aβ abnormality. These findings suggest that dynein dysfunction can alter neuronal activity via endocytic disturbances and may underlie age-dependent impairment of cognitive function. Moreover, in the presence of other risk factors such as intracellular Aβ accumulation and dynein dysfunction may contribute to the development of AD [209]. Defective transport of neuronal glutamate transporter mediated by Rab11 was linked to oxidative stress and cell death leading to neurodegeneration in Huntington's disease. Augmentation of Rab11 activity by using a dominant-active Rab11 mutant in primary Huntington's disease (HD) neurons improved the deficit in cysteine uptake, increased levels of intracellular glutathione and enhanced neuronal survival. Mutant Htt inhibits guanine nucleotide exchange on Rab11 in brains of young HD knock-in mice. Manipulation of Rab11 activity is beneficial for slowing the progression of HD as Rab11 is functionally



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distressed in several models of HD. Inhibition of Rab11 activity by mutant htt impairs vesicle formation from recycling endosomes in HD patient fibroblasts. Rab11 abrogated the loss of dendritic spines in primary murine neurons expressing mutant htt suggesting that Rab11 may play a critical early role in the synaptic dysfunction observed in HD. Furthermore, Rab11 overexpression reduced neurodegeneration in a fruit fly model of HD, and also extended lifespan and ameliorated defective emergence of the adult fly from the pupal case [210,211].

Type 2 diabetes Glucose is uptaken by insulin through translocation of the glucose transporter GLUT4 to the plasma membrane. In the basal state, GLUT4 interacts with cytosolic proteins within various endosomal recycling compartments. Depending on the unambiguous vesicles that GLUT4 travels through, several Rab GTPase family members are vital to this process. In case of type 2 diabetes, insulin resistance disrupts translocation of the intracellular resources of GLUT4 to the plasma membrane, in spite of normal GLUT4 expression, and consequently Rab proteins have come under inspection. Greater part of GLUT4 is retained as an active pool inside insulin receptive, and SNARES interacting cytoplasmic vesicles. Based on co localization studies of Rab GTPases in GLUT4 bound compartments, Rab4, Rab5, Rab8, Rab10, Rab11, Rab14 and Rab31 are involved in GLUT4 trafficking [212]. Nevertheless, illustrating any burly conclusion from the aforesaid observations is not possible because of the lacking of specific Rab antibodies, their overlapping locations and altered vesicular morphology. So far, Rab4, Rab5 and Rab11 are only functionally associated with GLUT4 trafficking [213,212]. Rab11 regulates the transport of GLUT4 from storage vesicles to the endocytic recycling pathway. While Rab4 has a complicated role in transporting GLUT4 under basal and insulin stimulated situations, and heterologous expressions of Rab4 facilitates retention of GLUT4 in the cytosol [214].

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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 expression have also been revealed in several models of human disease and in a variety of cancers. Upregulation of Rab1a, Rab4, Rab6 and altered Golgi morphology was observed in a β2adrenergic receptor model for cardiomyopathy, while increased expression of Rab7 was observed in a rabbit model for atherogenesis. Similarly in a mouse model for lung tumor progression increased expression of Rab2 was detected, whereas, in prostate cancer cell lines alterations in Rab25 expression were noted. Recent studies have identified that six Rab and three Arf/Sar proteins are upregulated in human liver cancers, including hepatocellular carcinomas and cholangiohepatomas. Thus, alterations in expression of a variety of Rab proteins as determined by gene expression profiling suggest that Rab proteins play a multitude of roles in maintaining normal cellular physiology. Based on the occurrence of altered Rab protein expression and/or regulation as a fundamental cause of human diseases, it is of significant interest in developing therapeutic entities from gene therapy to small molecule interventions, for restoring normal function or modulating pathways central to normal physiology. These are the huge challenges for drug discovery and delivery in near future [222,223].

Acknowledgment We would like to thank the reviewers for constructive feedback.

references Cancer Rab25, an epithelial-cell-specific member of the Rab GTPase superfamily, shares close homology with Rab11a. Several lines of evidences have indicated that Rab25 is involved in cancer progression. Its increased expression was seen in ovarian, breast and also in prostate cancers [215,216], in transitional cell carcinoma of the bladder [217] and in invasive breast tumor cells [218]. Recent reports indicate that it acts as both an oncogene and a tumor-suppressor gene. Rab25 has been shown to be involved in invasiveness of cancer cells by regulating integrin trafficking at cellular level. A critical role for Rab25 in cellular energetics has also been uncovered recently [219]. Another member of Rab11 family Rab11a, a novel tumor associated c-Fos/AP-1 target, may point to an as yet unrecognized function of Rab11a in the development of skin cancer [220]. In conclusion, the Rab GTPase family may be involved in a variety of disease settings including cancer progression. As the mechanisms of Rab GTPase actions are identified; the signalling and trafficking pathways in which they operate may present novel targets for therapeutic invention.

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Proteins affecting thylakoid morphology - the key to understanding vesicle transport in chloroplasts?

Key proteins involved in insulin vesicle exocytosis and secretion.

A novel chloroplast localized Rab GTPase protein CPRabA5e is involved in stress, development, thylakoid biogenesis and vesicle transport in Arabidopsis.

Intracellular transport of endocytosed proteins in rat liver endothelial cells.

Topological organization of proteins in an intracellular secretory organelle: the synaptic vesicle.

A family of proteins involved in intracellular transport.

Plasma membrane-located purine nucleotide transport proteins are key components for host exploitation by microsporidian intracellular parasites.

How Rab proteins determine Golgi structure.

RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions.

Functions of Rab Proteins at Presynaptic Sites.

MicroRNA: key gene expression regulators.

Rab proteins and gene family in animals.

Proteoglycans, key regulators of cell-matrix dynamics.

MicroRNAs are key regulators of brown adipogenesis.

αv integrins: key regulators of tissue fibrosis.

RAB-6.1 and RAB-6.2 Promote Retrograde Transport in C. elegans.

The autophagic roles of Rab small GTPases and their upstream regulators: a review.

SMYD proteins: key regulators in skeletal and cardiac muscle development and function.

The vesicle protein SAM-4 regulates the processivity of synaptic vesicle transport.

Spatiotemporal Regulators for Insulin-Stimulated GLUT4 Vesicle Exocytosis.

RAB-10 Regulates Dendritic Branching by Balancing Dendritic Transport.

RAB-10-Dependent Membrane Transport Is Required for Dendrite Arborization.

Rab GTPases: The Key Players in the Molecular Pathway of Parkinson's Disease.

“Deletion of both Rab-GTPase–activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport [corrected].