The TRAPP Complex Is a Nucleotide Exchanger for Ypt1 and Ypt31/32

Jones, Steven G.; Newman, Christina M.; Liu, Fengli; Segev, Nava

doi:10.1091/mbc.11.12.4403

Cited by 195 publications

(196 citation statements)

References 42 publications

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“…This is noteworthy because AEX-3 is the first exchange factor homologue found to regulate Rab27 in invertebrates or mammals. Also, few exchange factors have been shown to regulate multiple Rabs (Jones et al, 2000). Our findings also suggest that other mechanisms, in addition to exchange factors, specifically control different Rab functions.…”

Section: Discussionsupporting

confidence: 53%

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Mahoney

Liu

Itoh

et al. 2006

MBoC

159

218

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Rab small GTPases are involved in the transport of vesicles between different membranous organelles. RAB-3 is an exocytic Rab that plays a modulatory role in synaptic transmission. Unexpectedly, mutations in the Caenorhabditis elegans RAB-3 exchange factor homologue, aex-3, cause a more severe synaptic transmission defect as well as a defecation defect not seen in rab-3 mutants. We hypothesized that AEX-3 may regulate a second Rab that regulates these processes with RAB-3. We found that AEX-3 regulates another exocytic Rab, RAB-27. Here, we show that C. elegans RAB-27 is localized to synapse-rich regions pan-neuronally and is also expressed in intestinal cells. We identify aex-6 alleles as containing mutations in rab-27. Interestingly, aex-6 mutants exhibit the same defecation defect as aex-3 mutants. aex-6; rab-3 double mutants have behavioral and pharmacological defects similar to aex-3 mutants. In addition, we demonstrate that RBF-1 (rabphilin) is an effector of RAB-27. Therefore, our work demonstrates that AEX-3 regulates both RAB-3 and RAB-27, that both RAB-3 and RAB-27 regulate synaptic transmission, and that RAB-27 potentially acts through its effector RBF-1 to promote soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) function. INTRODUCTIONNeurotransmitter release is accomplished by the fusion of neurotransmitter-filled synaptic vesicles at the presynaptic nerve terminal. This process occurs through a series of highly regulated steps that include synaptic vesicle transport, docking/tethering, priming, fusion, endocytosis, recycling, and neurotransmitter refilling (Sudhof, 2004). Several genes have been assigned roles in the various steps of the synaptic vesicle cycle. Rab3 (termed RAB-3 in Caenorhabditis elegans), a member of the Rab family of small GTPases, regulates synaptic transmission, possibly through the docking, priming, or fusion steps Schluter et al., 2004).Rabs act in a variety of cell types and regulate vesicular transport between organelles. Rabs cycle on and off membranes via a GTP-dependent mechanism (Zerial and McBride, 2001). Rab activity is regulated by two proteins, which act in an antagonistic manner. The guanine nucleotide exchange factor (GEF) exchanges GTP for GDP, and the GTPase activating protein activates the intrinsic GTPase activity of a Rab (Bernards, 2003). GDP bound Rabs are held off of the membrane by a GDP dissociation inhibitor (Wu et al., 1996). The GTP/membrane-bound form of Rabs typically binds to a variety of effectors that regulate particular steps of membrane transport and cell signaling (Zerial and McBride, 2001;Spang, 2004).Rab3 was once thought to play a central role in regulating release. However, recent work has shown that a quadruple knockout of all four isoforms of Rab3 in mice only results in a 30% reduction in evoked synaptic response (Schluter et al., 2004). This is consistent with work in C. elegans showing that mutations in the single rab-3 gene cause only mild defects in synaptic transmission . Surprisingly, more dramatic phe...

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Section: Discussionsupporting

confidence: 53%

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Mahoney

Liu

Itoh

et al. 2006

MBoC

159

218

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“…In a recent study, the Golgiassociated Hrr25 kinase was reported to phosphorylate Sec23/Sec24 and regulate interactions between Sec23 and TRAPPI to control directionality of anterograde transport (Lord et al 2011). Moreover, TRAPPI functions as a GEF for Ypt1 in a manner that is thought to generate activated Ypt1 on the surface of Golgi acceptor membranes and/or COPII vesicles (Jones et al 2000;Wang et al 2000;Lord et al 2011). A subassembly of TRAPPI consisting of Bet3, Bet5, Trs23, and Trs31 binds Ypt1p and catalyzes nucleotide exchange by stabilizing an open form of this GTPase (Cai et al 2008).…”

Section: Vesicle Tetheringmentioning

confidence: 99%

Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

2013

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The secretory pathway is responsible for the synthesis, folding, and delivery of a diverse array of cellular proteins. Secretory protein synthesis begins in the endoplasmic reticulum (ER), which is charged with the tasks of correctly integrating nascent proteins and ensuring correct post-translational modification and folding. Once ready for forward traffic, proteins are captured into ER-derived transport vesicles that form through the action of the COPII coat. COPII-coated vesicles are delivered to the early Golgi via distinct tethering and fusion machineries. Escaped ER residents and other cycling transport machinery components are returned to the ER via COPI-coated vesicles, which undergo similar tethering and fusion reactions. Ultimately, organelle structure, function, and cell homeostasis are maintained by modulating protein and lipid flux through the early secretory pathway. In the last decade, structural and mechanistic studies have added greatly to the strong foundation of yeast genetics on which this field was built. Here we discuss the key players that mediate secretory protein biogenesis and trafficking, highlighting recent advances that have deepened our understanding of the complexity of this conserved and essential process. TABLE OF CONTENTS Abstract 383Introduction 384

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“…When stimulated by exchange factors termed "guanine nucleotide exchange factors" (GEFs), they interact with multiple downstream effectors, which mediate the different steps of vesicular trafficking (1,2). In yeast, Ypt1 is required for endoplasmic reticulum (ER)-toGolgi transport (3)(4)(5), and the TRAPP I complex acts as its GEF (6,7). Rab1, the human functional homolog of Ypt1, also plays a role in ER-to-Golgi transport (8,9).…”

mentioning

confidence: 99%

Regulation of selective autophagy onset by a Ypt/Rab GTPase module

Lipatova¹,

Belogortseva

Zhang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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117

180

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The key regulators of intracellular trafficking, Ypt/Rab GTPases, are stimulated by specific upstream activators and, when activated, recruit specific downstream effectors to mediate membrane-transport events. The yeast Ypt1 and its human functional homolog hRab1 regulate both endoplasmic reticulum (ER)-to-Golgi transport and autophagy. However, it is not clear whether the mechanism by which these GTPases regulate autophagy depends on their well-documented function in ER-to-Golgi transport. Here, we identify Atg11, the preautophagosomal structure (PAS) organizer, as a downstream effector of Ypt1 and show that the Ypt1-Atg11 interaction is required for PAS assembly under normal growth conditions. Moreover, we show that Ypt1 and Atg11 colocalize with Trs85, a Ypt1 activator subunit, and together they regulate selective autophagy. Finally, we show that Ypt1 and Trs85 interact on Atg9-containing membranes, which serve as a source for the membrane component of the PAS. Together our results define a Ypt/Rab module-comprising an activator, GTPase, and effector-that orchestrates the onset of selective autophagy, a process vital for cell homeostasis. Furthermore, because Atg11 does not play a role in ER-to-Golgi transport, we demonstrate here that Ypt/Rabs can regulate two independent membrane-transport processes by recruiting process-specific effectors.

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The TRAPP Complex Is a Nucleotide Exchanger for Ypt1 and Ypt31/32

Cited by 195 publications

References 42 publications

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Regulation of Synaptic Transmission by RAB-3 and RAB-27 inCaenorhabditis elegans

Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

Regulation of selective autophagy onset by a Ypt/Rab GTPase module

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