Guanine Nucleotide Exchange Factors (GEFs) Have a Critical but Not Exclusive Role in Organelle Localization of Rab GTPases

Cabrera, Margarita; Ungermann, Christian

doi:10.1074/jbc.m113.488213

Cited by 70 publications

(85 citation statements)

References 54 publications

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“…In agreement with this, the exclusive vacuolar localization of Ypt7 was lost in both mutants, as observed for the GEF deletion strains (Fig. 3A) (Cabrera and Ungermann, 2013). We next asked whether the observed defect was due to complex assembly.…”

Section: Mon1 and Ccz1 Require A Common Interface For Ypt7 Activationsupporting

confidence: 59%

The Mon1-Ccz1 GEF activates the Rab7 GTPase Ypt7 via a longin fold-Rab interface and association with PI-3-P-positive membranes

Cabrera

Nordmann

Perz

et al. 2014

Journal of Cell Science

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103

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To function in fusion and signaling, Rab GTPases need to be converted into their active GTP form. We previously identified the conserved Mon1-Ccz1 complex as the guanine nucleotide exchange factor (GEF) of the yeast Rab7 GTPase Ypt7. To address the possible GEF mechanism, we generated a homology model of the predicted longin domains of Mon1 and Ccz1 using the Rabbinding surface of the TRAPP complex as a template. On the basis of this, we identified mutations in both yeast Mon1 and Ccz1 that block Ypt7 activation, without affecting heterodimer formation and intracellular localization of Mon1 and Ccz1 at endosomes. Strikingly, the activity of the isolated Mon1-Ccz1 complex for Ypt7 is highly stimulated on membranes, and is promoted by the same anionic phospholipids such as phosphatidylinositol-3-phosphate (PI3P), which also support membrane association of the GEF complex. Our data imply that the GEF activity of the Mon1-Ccz1 complex towards Rab7/Ypt7 requires the interface formed by their longin domains and profits strongly from its association with the organelle surface.

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Section: Mon1 and Ccz1 Require A Common Interface For Ypt7 Activationsupporting

confidence: 59%

The Mon1-Ccz1 GEF activates the Rab7 GTPase Ypt7 via a longin fold-Rab interface and association with PI-3-P-positive membranes

Cabrera

Nordmann

Perz

et al. 2014

Journal of Cell Science

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103

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“…We observed an enhanced vesicular as well as PM localization of VPS9a-GFP at early time points after salt stress. Recent studies have shown that the membrane localization and activity of Rab-GEFs are crucial factors in regulating the localization and specificity of downstream Rab-GTPases (Blümer et al, 2013;Cabrera and Ungermann, 2013). Rab-GEFs are also subject to activation by signaling cascades that regulate their membrane localization and subsequent endocytosis events (Tall et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Salt-Induced Remodeling of Spatially Restricted Clathrin-Independent Endocytic Pathways in Arabidopsis Root

et al. 2015

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Endocytosis is a ubiquitous cellular process that is characterized well in animal cells in culture but poorly across intact, functioning tissue. Here, we analyze endocytosis throughout the Arabidopsis thaliana root using three classes of probes: a lipophilic dye, tagged transmembrane proteins, and a lipid-anchored protein. We observe a stratified distribution of endocytic processes. A clathrin-dependent endocytic pathway that internalizes transmembrane proteins functions in all cell layers, while a sterol-dependent, clathrin-independent pathway that takes up lipid and lipid-anchored proteins but not transmembrane proteins is restricted to the epidermal layer. Saline stress induces a third pathway that is clathrinindependent, nondiscriminatory in its choice of cargo, and operates across all layers of the root. Concomitantly, small acidic compartments in inner cell layers expand to form larger vacuole-like structures. Plants lacking function of the Rab-GEF (guanine nucleotide exchange factor) VPS9a (vacuolar protein sorting 9A) neither induce the third endocytic pathway nor expand the vacuolar system in response to salt stress. The plants are also hypersensitive to salt. Thus, saline stress reconfigures clathrin-independent endocytosis and remodels endomembrane systems, forming large vacuoles in the inner cell layers, both processes correlated by the requirement of VPS9a activity.

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“…For example, DENN/MADD/ Rab3GEP does not exhibit any membrane localization (presumably present in the cytosol), whereas its substrate Rab27A clearly localizes on mature melanosomes in melanocytes and on amylase-containing secretory granules in parotid acinar cells (Figueiredo et al, 2008;Imai et al, 2013). Moreover, a Ypt7p mutant with a unique mutation (K127E), which may increase the efficiency of nucleotide exchange of Ypt7p, is able to localize on vacuoles even in GEF (Mon1-Ccz1)-deficient cells, suggesting that additional factors contribute to the vacuole localization of Ypt7p in budding yeasts (Cabrera and Ungermann, 2013). An in depth analysis of the relationship between the localization of each GEF and its substrate Rab(s) will be necessary to determine whether GEF localization is the major determinant of the localization of most Rabs.…”

Section: Relationships Between Localization Of Gef and Rab Recruitmentmentioning

confidence: 99%

“…One of the controversial issues in the area of TRAPP research is whether the TRAPP II complex acts as a GEF for the yeast Rab11 homologues Ypt31p and Ypt32p. In fact, several groups have shown that the TRAPP II complex functions as a specific GEF for Rab11 homologues in S. cerevisiae and Aspergillus nidulans (Morozova et al, 2006;Cabrera and Ungermann, 2013;Pinar et al, 2015).…”

Section: Trapp Complexesmentioning

confidence: 99%

Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

Ishida

Oguchi

Fukuda

2016

Cell Struct. Funct.

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ABSTRACT. Rab small GTPases are highly conserved master regulators of membrane traffic in all eukaryotes. The same as the activation and inactivation of other small GTPases, the activation and inactivation of Rabs are tightly controlled by specific GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins), respectively. Although almost all Rab-GAPs reported thus far have a TBC (Tre-2/Bub2/Cdc16)/Rab-GAP domain in common, recent accumulating evidence has indicated the existence of a number of structurally unrelated types of Rab-GEFs, including DENN proteins, VPS9 proteins, Sec2 proteins, TRAPP complexes, heterodimer GEFs (Mon1-Ccz1, HPS1-HPS4 (BLOC-3 complex), Ric1-Rgp1 and Rab3GAP1/2), and other GEFs (e.g., REI-1 and RPGR). In this review article we provide an up-to-date overview of the structures and functions of all putative Rab-GEFs in mammals, with a special focus on their substrate Rabs, interacting proteins, associations with genetic diseases, and intracellular localizations.

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Guanine Nucleotide Exchange Factors (GEFs) Have a Critical but Not Exclusive Role in Organelle Localization of Rab GTPases

Cited by 70 publications

References 54 publications

The Mon1-Ccz1 GEF activates the Rab7 GTPase Ypt7 via a longin fold-Rab interface and association with PI-3-P-positive membranes

The Mon1-Ccz1 GEF activates the Rab7 GTPase Ypt7 via a longin fold-Rab interface and association with PI-3-P-positive membranes

Salt-Induced Remodeling of Spatially Restricted Clathrin-Independent Endocytic Pathways in Arabidopsis Root

Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

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