Rab GTPase regulation of membrane identity

Abstract

A fundamental question in cell biology is how cells determine membrane compartment identity and the directionality with which cargoes pass through the secretory and endocytic pathways. The discovery of so-called 'Rab cascades' provides a satisfying molecular mechanism that helps to resolve this paradox. One Rab GTPase has the ability to template the localization of the subsequent acting Rab GTPase along a given transport pathway. Thus, in addition to determining compartment identity and functionality, Rab GTPases are likely able to order the events of membrane trafficking. This review will highlight recent advances in our understanding of Rabs and Rab cascades.

Figure 1

Prenylated Rab GTPases are delivered to membranes by GDI in their GDP-bound forms in a process that may be facilitated by a GDI-displacement factor (GDF). Guanine nucleotide exchange factors (GEFs) catalyze the release of bound GDP to permit GTP binding. Rab-GTP can be stabilized on membranes by binding to cognate effectors. GDI in cytosol can retrieve Rabs delivered to incorrect membranes unless they encounter their cognate GEF at that location.

Figure 2

Heterodimeric Rab GEFs recruit subsequent acting Rabs as part of Rab cascades. A. On early endosomes, Rab5 recruits the kinase that generates phosphatidylinositol 3-phosphate (PI3P); Ccz1/Mon1 is then recruited to membranes containing Rab5-GTP [30] and PI3P [31]. Ccz1/Mon1 catalyzes the release of GDP from Rab7A [29; 25], thereby permitting the entry of GTP. Presumably a Rab5 GAP will be identified that is a Rab7A effector to help clear Rab5 from a newly formed, Rab7A membrane microdomain. Ccz1/Mon1 also displaces the Rab5 GEF, Rabex-5, from membranes [31]. B. On the Golgi, medial Golgi Rab33B recruits the Ric1/Rgp1 GEF for Rab6A [28]. On late endosomes, the Hps1/Hps4 GEF for Rab32 [25] is recruited to late endosomes by Rab9A [32]. D. Rab9A can also recruit RUTBC1, a GTPase activating protein that inactivates Rab32 [33]. Rab32 GDP would be a target for membrane extraction by cytoplasmic GDI protein. This would counteract the reaction in C and may be restricted to specific tissues and/or cell types.