TBC-8, a Putative RAB-2 GAP, Regulates Dense Core Vesicle Maturation in Caenorhabditis elegans
| Autor: | Nikhil Sasidharan, Sabine Koenig, Lena M. Kutscher, Stefan Eimer, Mandy Hannemann, Jan Hegermann |
|---|---|
| Přispěvatelé: | Goodman, Miriam B. |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
GTPase-activating protein rab3 GTP-Binding Proteins Golgi Apparatus GTPase Autoantigens 0302 clinical medicine Molecular Cell Biology Dense core vesicles DCV maturation Genetics (clinical) Caenorhabditis elegans Motor Neurons 0303 health sciences Effector GTPase-Activating Proteins Clathrin-Coated Vesicles Animal Models Cell biology Protein Transport Caenorhabditis Elegans symbols Membranes and Sorting Research Article lcsh:QH426-470 Endosome Endosomes Biology Signaling Pathways 03 medical and health sciences symbols.namesake Model Organisms Genetics Animals Humans Caenorhabditis elegans Proteins Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Secretory Vesicles Golgi apparatus biology.organism_classification rab2 GTP-Binding Protein lcsh:Genetics Gene Expression Regulation Membrane protein Rab Molecular Neuroscience 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS Genetics, Vol 8, Iss 5, p e1002722 (2012) PLoS Genetics |
| Popis: | Dense core vesicles (DCVs) are thought to be generated at the late Golgi apparatus as immature DCVs, which subsequently undergo a maturation process through clathrin-mediated membrane remodeling events. This maturation process is required for efficient processing of neuropeptides within DCVs and for removal of factors that would otherwise interfere with DCV release. Previously, we have shown that the GTPase, RAB-2, and its effector, RIC-19, are involved in DCV maturation in Caenorhabditis elegans motoneurons. In rab-2 mutants, specific cargo is lost from maturing DCVs and missorted into the endosomal/lysosomal degradation route. Cargo loss could be prevented by blocking endosomal delivery. This suggests that RAB-2 is involved in retention of DCV components during the sorting process at the Golgi-endosomal interface. To understand how RAB-2 activity is regulated at the Golgi, we screened for RAB-2–specific GTPase activating proteins (GAPs). We identified a potential RAB-2 GAP, TBC-8, which is exclusively expressed in neurons and which, when depleted, shows similar DCV maturation defects as rab-2 mutants. We could demonstrate that RAB-2 binds to its putative GAP, TBC-8. Interestingly, TBC-8 also binds to the RAB-2 effector, RIC-19. This interaction appears to be conserved as TBC-8 also interacted with the human ortholog of RIC-19, ICA69. Therefore, we propose that a dynamic ON/OFF cycling of RAB-2 at the Golgi induced by the GAP/effector complex is required for proper DCV maturation. Author Summary Synaptic transmission is mainly mediated by the triggered release of neurotransmitters from synaptic vesicles (SVs). To regulate synaptic transmission and neuronal activity, neurons also release neuropeptides and hormones from dense core vesicles (DCVs). While SVs can be recycled locally at the synapse, DCVs have to be newly synthesized in the cell body after release. The formation of new DCVs requires a multi-step maturation process. During this maturation, the neuropeptides are processed into their active form and factors that would disturb DCV release are removed. Only properly matured DCVs are able to undergo efficient release after stimulation. Since DCV biogenesis mainly uses the normal secretory pathway, an elaborate machinery must exist that guarantees efficient sorting and retention of DCV cargo. Previously, we identified the small GTPase RAB-2 and its effector RIC-19/ICA69 to be involved in the retention of soluble cargo in DCVs. In a screen for molecules that regulate RAB-2 activity during DCV maturation, we identified the evolutionarily conserved TBC domain-containing protein, TBC-8. We demonstrate that TBC-8 is a putative RAB-2 GAP, which also binds to RIC-19/ICA69. Thus, RAB-2 might recruit its own GAP via its effector RIC-19, which suggests that a highly dynamic cycling of RAB-2 is required for DCV maturation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|