Rab GTPase localization and Rab cascades in Golgi transport

Abstract

Rab GTPases are master regulators of membrane traffic. By binding to distinct sets of effector proteins, Rabs catalyse the formation of function-specifying membrane microdomains. They are delivered to membranes by a protein named GDI (guanine-nucleotide-dissociation inhibitor) and are stabilized there after nucleotide exchange by effector binding. In the present mini-review, I discuss what we know about how Rab GTPases are delivered to the correct membrane-bound compartments and how Rab GTPase cascades order Rabs within the secretory and endocytic pathways. Finally, I describe how Rab cascades may establish the distinct compartments of the Golgi complex to permit ordered processing, sorting and secretion of secretory cargoes.

Figure 1. A model for Rab recruitment on to membranes

GDP-bound Rabs are recruited to membranes from cytosolic complexes with GDI through the catalytic action of a GDF. GEF catalyses nucleotide exchange. Interaction of the Rab-GTP with an effector that has been recruited to the same membrane by a Rab (option A) or by an effector binding partner (option B) will stabilize both the Rab and the effector on the membrane. If not bound to the effector, a GAP can activate the Rab to hydrolyse its GTP to GDP, thus allowing for potential membrane extraction of the Rab by GDI. Thus the Rab GTPase is dependent on its effectors, and vice versa, for stable interaction with the membrane. The effector binding partner need not be a protein and can be particular phospholipids, such as phosphoinositides, that are specific to a given compartment. © 2006 Rockefeller University Press. Reproduced from Aivazian, D., Serrano, R.L. and Pfeffer, S. (2006) TIP47 is a key effector for Rab9 localization. J. Cell Biol. 173, 917–926 with permission.

Figure 2. A cisternal progenitor model for transport through the Golgi

Transport through the Golgi and Golgi stack creation in a cisternal progenitor model. (A) Premise 1 states that Golgi stacks undergo continuous reversible fission and fusion. Consider a stably stacked Golgi where each cisterna is marked by a different Rab protein. The stack can grow if a Rab cascade builds sequential domains that can fuse with like domains (e.g. RabB regions with other RabB regions). RabA will create an adjacent RabB domain that may segregate by fission within the stack. The RabB bleb would fuse with the stable RabB cisterna, thereby growing. (B) This process can include cargo. Alternatively (or simultaneously), vesicles may carry cargo from a RabA compartment to a RabB compartment by ‘heterotypic fusion’. Importantly, the RabA compartment is stable and is the progenitor of the RabB compartment. (C) The RabB compartment has the capacity to remove RabA for redelivery to the cis-Golgi. (D) The Golgi vesiculates in cells lacking the homotypic fusion factor p37 [23]. Reproduced from Pfeffer, S.R. (2010) How the Golgi works: a cisternal progenitor model. Proc. Natl. Acad. Sci. U.S.A. 107, 19614–19618 with permission. © 2010 National Academy of Sciences U.S.A.