Role of Rab GTPases in membrane traffic and cell physiology - PubMed (original) (raw)

Review

Role of Rab GTPases in membrane traffic and cell physiology

Alex H Hutagalung et al. Physiol Rev. 2011 Jan.

Abstract

Intracellular membrane traffic defines a complex network of pathways that connects many of the membrane-bound organelles of eukaryotic cells. Although each pathway is governed by its own set of factors, they all contain Rab GTPases that serve as master regulators. In this review, we discuss how Rabs can regulate virtually all steps of membrane traffic from the formation of the transport vesicle at the donor membrane to its fusion at the target membrane. Some of the many regulatory functions performed by Rabs include interacting with diverse effector proteins that select cargo, promoting vesicle movement, and verifying the correct site of fusion. We describe cascade mechanisms that may define directionality in traffic and ensure that different Rabs do not overlap in the pathways that they regulate. Throughout this review we highlight how Rab dysfunction leads to a variety of disease states ranging from infectious diseases to cancer.

PubMed Disclaimer

Conflict of interest statement

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

Figures

FIG. 1

FIG. 1

The intracellular localization of Rabs. A typical cell showing the intracellular localization and associated vesicle transport pathway(s) of several Rab GTPases. Rab1 regulates ER-Golgi traffic while Rab2 is involved in recycling, or retrograde traffic, from Golgi and the ERGIC back to the ER. Rab6 regulates intra-Golgi traffic. Several Rabs including Rab8, -10, and -14 regulate biosynthetic traffic from the _trans_-Golgi network (TGN) to the plasma membrane. The glucose transporter GLUT4 is found in vesicles that use these Rabs to reach the plasma membrane. Several secretory vesicles and granules use Rab3, -26, -27, and -37 to exocytose their cargo. Rab27 is well-studied in the melanosome transport that also relies on Rabs 32 and 38. There are numerous Rabs associated with endosomal traffic, and the most active site of localization is the early endosome. Most early endocytic steps rely on Rab5, which mediates fusion of endocytic vesicles to form the early endosome. Traffic can be directed towards the lysosome for degradation, which relies on action of Rab7, or to various recycling compartments to return factors to the plasma membrane. Rab15 directs membrane traffic from the early endosome to the recycling endosome. Rab4 and Rab11 regulate fast and slow endocytic recycling, respectively. Specialized Rab functions include Rab18-mediated regulation of lipid droplets, intracellular lipid storage sites. Rab24 and Rab33 mediate formation of the preautophagosomal structure that engulfs cellular components to form the autophagosome that is subsequently targeted to the lysosome/vacuole. Rab21 and Rab25 regulate transport of integrins to control cell adhesion and cytokinesis. Rab13 directs traffic to and regulates formation of tight junctions in polarized epithelial cells. Tight junctions define the boundary between the apical and basolateral regions of the polarized cell. Mutations in the mouse Rab23 gene lead to a severe developmental defect, open brain, because Rab23 acts downstream to negatively regulate Sonic hedgehog (Shh) signaling during dorsoventral development of the mouse spinal cord. It potentially interacts with the transcription factors activated by the Shh pathway. Rab40 also acts in a signaling pathway; it recruits components of the ubiquitination machinery to regulate Wnt signaling. There are several poorly characterized Rabs, such as Rab35. It controls plasma membrane recycling of an essential factor in cytokinesis. Rab34 and Rab39 are found on the Golgi, but it is unclear what role they play. AP, autophagosome; ERGIC, ER-Golgi intermediate compartment; ER, endoplasmic reticulum; EE, early endosome; LD, lipid droplet; LE, late endosome (multivesicular body); L/V, lysosome/vacuole; PAS, preautophagosomal structure; RE, recycling endosome; SV, secretory vesicle/granule.

FIG. 2

FIG. 2

The Rab cycle. The newly synthesized Rab protein associates with Rab escort protein (REP) that directs it to Rab geranylgeranyl transferase (RabGGT) to receive its prenyl tails (red wavy lines). REP delivers the Rab to its target membrane. Throughout this process, the Rab is GDP-bound. A guanine nucleotide exchange factor (GEF) catalyzes exchange of GDP for GTP to activate the Rab. The GTP-bound Rab interacts with effector proteins that mediate membrane traffic in the pathway regulated by its associated Rab. The Rab then interacts with its associated GTPase activating protein (GAP) that catalyzes hydrolysis of GTP to GDP by the Rab. The Rab is then removed from the membrane by guanine nucleotide dissociation inhibitor (GDI) in preparation for the next cycle. The insertion of the Rab into the target membrane is mediated by a GDI dissociation factor (GDF) that releases the Rab from GDI. Loss-of-function mutations at each of the above steps produce disease phenotypes as indicated by the red text boxes.

FIG. 3

FIG. 3

Rab effectors. Rabs perform their regulatory function by recruiting a variety of effectors to mediate different functions in membrane transport. These functions are as follows: 1) cargo selection/budding/coat formation, 2) vesicle transport, 3) vesicle uncoating/tethering, and 4) vesicle fusion. Below each function are examples of Rab effectors that perform said function. Mutations in Rab effectors also lead to disease phenotypes: Griscelli Syndrome is caused by mutations in either Rab27A, the Rab27A effector protein melanophilin, or myosin VA, while congenital disorders of glycosylation and spondyloepiphyseal dysplasia tarda (SEDT) are caused by mutations in several COG subunits (COG1, COG7, and COG8) and the TRAPP subunit Trs20, respectively.

FIG. 4

FIG. 4

The Rab GEF and GAP cascade. Once RabA inserts into its target membrane, it is activated by its respective GEF (step 1). Activated RabA recruits the GEF for the downstream Rab in the pathway RabB (step 2). GTP-bound RabB performs two functions: it recruits the GAP to inactivate RabA (step 3) as well as the GEF for the downstream Rab, RabC (step 4). Activated RabC now recruits the GAP that inactivates RabB (step 5). The concomitant action of GAPs and GEFs ensures the boundaries of each membrane compartment, determined by the actions of their associated Rab, are well-defined.

Similar articles

Cited by

References

    1. Aivazian D, Serrano R, Pfeffer S. TIP47 is a key effector for Rab9 localization. J Cell Biol. 2006;173:917–926. - PMC - PubMed
    1. Alexandrov K, Horiuchi H, Steele-Mortimer O, Seabra M, Zerial M. Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes. EMBO J. 1994;13:5262–5273. - PMC - PubMed
    1. Ali B, Seabra M. Targeting of Rab GTPases to cellular membranes. Biochem Soc Trans. 2005;33:652–656. - PubMed
    1. Aligianis I, Johnson C, Gissen P, Chen D, Hampshire D, Hoffmann K, Maina E, Morgan N, Tee L, Morton J, Ainsworth J, Horn D, Rosser E, Cole T, Stolte-Dijkstra I, Fieggen K, Clayton-Smith J, Mégarbané A, Shield J, Newbury-Ecob R, Dobyns W, Graham JJ, Kjaer K, Warburg M, Bond J, Trembath R, Harris L, Takai Y, Mundlos S, Tannahill D, Woods C, Maher E. Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet. 2005;37:221–223. - PubMed
    1. Aligianis I, Morgan N, Mione M, Johnson C, Rosser E, Hennekam R, Adams G, Trembath R, Pilz D, Stoodley N, Moore A, Wilson S, Maher E. Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am J Hum Genet. 2006;78:702–707. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources