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Review
. 2013 Jul 22;202(2):191-9.
doi: 10.1083/jcb.201306010.

Review series: Rab GTPases and membrane identity: causal or inconsequential?

Francis A Barr  1
Affiliations
Review

Review series: Rab GTPases and membrane identity: causal or inconsequential?

Francis A Barr. J Cell Biol. .

Abstract

Rab GTPases are highly conserved components of vesicle trafficking pathways that help to ensure the fusion of a vesicle with a specific target organelle membrane. Specific regulatory pathways promote kinetic proofreading of membrane surfaces by Rab GTPases, and permit accumulation of active Rabs only at the required sites. Emerging evidence indicates that Rab activation and inactivation are under complex feedback control, suggesting that ultrasensitivity and bistability, principles established for other cellular regulatory networks, may also apply to Rab regulation. Such systems can promote the rapid membrane accumulation and removal of Rabs to create time-limited membrane domains with a unique composition, and can explain how Rabs define the identity of vesicle and organelle membranes.

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Figures

Figure 1.
Figure 1.
The Rab activation and inactivation cycle. (A) Prenylated Rabs (black wavy lines) are bound by the chaperone GDI in the cytosol. Partitioning of the prenylated tail moiety between the hydrophobic pocket in GDI and the membrane bilayer allows Rabs to rapidly and reversibly sample membrane surfaces. When the GDP-bound inactive Rab encounters a cognate GEF nucleotide exchange occurs. This GTP-bound active Rab species does not interact with GDI and can therefore accumulate on the membrane surface, where it may further recruit effector proteins with specific biological functions. This cycle is reset when a GTP-bound Rab encounters a GAP (GTPase-activating protein) and the bound GTP is hydrolyzed to generate GDP and inorganic phosphate. (B) Additional specification of membrane domains within complex organelles, such as tubular domains of endosomes, or the fenestrated rims and different cisternae of the Golgi apparatus, may involve membrane receptors for Rabs (shown as light blue, dark blue, and green boxes). This could either involve (a) sequestration of the active Rab to a subdomain defined by the membrane receptor, or (b) direction of GDI unloading of an inactive Rab to specific sites on the organelle membrane also defined by a membrane receptor. Accumulation of a Rab at a specific site may be favored by GAPs opposing Rab activation at unwanted sites (Haas et al., 2007).
Figure 2.
Figure 2.
Recruitment mechanisms for Rab GEFs. Rab GEFs can be divided into two groups according to the mechanism of membrane recruitment. (A) Discrete coat protein complexes (green) recruit the first group. For example, COP II recruits the Rab1 GEF TRAPP to ER-Golgi vesicles, while clathrin-AP2 recruits DENND1A, the Rab35 GEF, to endocytic sites at the cell surface. In the case of TRAPP, biochemical and genetic data suggest that Rab1 can be activated on the target membrane, before vesicle tethering and SNARE-mediated fusion. (B) The larger second group of Rab GEFs is recruited by Rab GTPases either alone or in combination with a second factor (Rabs/factors listed next to arrow). For example, the GEF Sec2 is recruited to late-Golgi vesicles trafficking to the bud in yeast by the activated Rab Ypt31/32 and phosphatidylinositol 4-phosphate (PI4P), where it activates the Rab Sec4 (Rab8 in humans). The Rabex5–rabaptin complex, which is a Rab5 GEF, interacts with activated Rab4 or Rab5 and ubiquitylated cargo proteins on endocytic vesicles and early endosomes. A number of other GEFs (some additional examples shown) have been found to interact with active Rabs. Whether or not these represent the sole mode of membrane interaction for these GEFs is not defined at this time. PM, plasma membrane. (C) In situations where the GEF for a second Rab in the pathway is an effector for the first, a cascade can develop, where Rab-A promotes the recruitment of GEF-B for this second Rab-B.
Figure 3.
Figure 3.
Ultrasensitivity and bistability in Rab regulatory networks. (A) A simplified schematic of a Rab activation cycle is shown treating GDP–GTP exchange as equivalent to a covalent modification cycle such as phosphorylation. Because the reaction can only occur at a membrane surface, membrane recruitment factors are treated as activating inputs. Assuming no feedback and normal first-order reaction kinetics, Rab recruitment would be expected to follow Michaelis-Menten behavior. In cases where substrate is saturating and the reaction becomes zero-order, Goldbeter and Koshland (1984) have shown that product formation becomes more sensitive to enzyme concentration. In this case, generation of GTP-bound Rab becomes ultrasensitive to GEF concentration at the membrane surface. If additional positive feedback controls exist as shown in the bottom panel, then bistability may develop. In this case a rapid switch-like transition in Rab activity develops as Rab GEF concentration increases. Once in the active state the system becomes less dependent on continued high GEF activity. (B) A model for an interlinked Rab cascade is shown. The GEF for Rab-B is an effector for activated Rab-A, while the GAP for Rab-A is regulated by Rab-B. An example of this latter situation is provided by the Ypt1–Yp32 system discussed in the main text and shown in the bottom panel, where a Ypt1 GAP Gyp1 is an effector for Ypt32 (Rivera-Molina and Novick, 2009) and inhibits Ypt1. This coupling of the two cycles can result in coupled ultrasensitive switch-like transitions or bistability.
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