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CD63, a member of the tetraspanin family, is involved in virion production by human immunodeficiency virus type 1 (HIV-1), but its mechanism is unknown. In this study, we showed that a small GTP-binding protein, Rab3a, interacts with CD63. When Rab3a was exogenously expressed, the amounts of CD63 decreased in cells. The Rab3a-mediated reduction of CD63 was suppressed by lysosomal and proteasomal inhibitors. The amount of CD63 was increased by reducing the endogenous Rab3a level using a specific shRNA. These results indicate that Rab3a binds to CD63 to induce the degradation of CD63. Rab3a is thought to be involved in exocytosis, but we found that another function of Rab3a affects the fate of CD63 in lysosomes. CD63 interacted with Rab3a and was incorporated into HIV-1 particles. However, Rab3a was not detected in HIV-1 virions, thereby indicating that Rab3a-free CD63, but not Rab3a-bound CD63, is incorporated into HIV-1 particles. Overexpression or silencing of Rab3a moderately reduced HIV-1 virion formation. Overexpression of Rab3a decreased CD63 levels, but did not affect the incorporation of CD63 into HIV-1 particles. This study showed that Rab3a binds to CD63 to induce the degradation of CD63, and only Rab3a-free CD63 is incorporated into HIV-1 particles.
Neurogenin 3 (NGN3) commits pancreatic progenitors to an islet cell fate. We have induced NGN3 expression and identified upregulation of the gene encoding the Ras-associated small molecular mass GTP-binding protein, RAB3B. RAB3B localised to the cytoplasm of human β-cells, both during the foetal period and post natally. Genes encoding alternative RAB3 proteins and RAB27A were unaltered by NGN3 expression and in human adult islets their transcripts were many fold less prevalent than those of RAB3B. The regulation of insulin exocytosis in rodent β-cells and responsiveness to incretins are reliant on Rab family members, notably Rab3a and Rab27a, but not Rab3b. Our results support an important inter-species difference in regulating insulin exocytosis where RAB3B is the most expressed isoform in human islets.
Ras-associated binding (Rab) protein 3A is a neuronal guanosine triphosphate (GTP)-binding protein that binds synaptic vesicles and regulates synaptic transmission. A mouse mutant, earlybird (Ebd), with a point mutation in the GTP-binding domain of Rab3A (D77G), exhibits anomalies in circadian behavior and homeostatic response to sleep loss. Here, we show that the D77G substitution in the Ebd allele causes reduced GTP and GDP binding, whereas GTPase activity remains intact, leading to reduced protein levels of both Rab3A and rabphilin3A. Expression profiling of the cortex and hippocampus of Ebd and Rab3a-deficient mice revealed subtle differences between wild-type and mutant mice. Although mice were backcrossed for three generations to a C57BL/6J background, the most robust changes at the transcriptional level between Rab3a(-/-) and Rab3a(+/+) mice were represented by genes from the 129/Sv-derived chromosomal region surrounding the Rab3a gene. These results showed that differences in genetic background have a stronger effect on gene expression than the mutations in the Rab3a gene. In behavioral tests, the Ebd/Ebd mice showed a more pronounced mutant phenotype than the null mice; Ebd/Ebd have reduced anxiety-like behavior in the elevated zero-maze test, reduced response to stress in the forced swim test and a deficit in cued fear conditioning (FC), whereas Rab3a(-/-) showed only a deficit in cued FC. Our data implicate Rab3A in learning and memory as well as in the regulation of emotion. A combination of forward and reverse genetics has provided multiple alleles of the Rab3a gene; our studies illustrate the power and complexities of the parallel analysis of these alleles at the biochemical, molecular and behavioral levels.
Rab3A, a small GTP-binding protein attached to synaptic vesicles, has been implicated in several stages in the process of neurosecretion, including a late stage occurring just prior to the actual release of neurotransmitter. The inhibitory neuromodulator adenosine also targets a late step in the neurosecretory pathway. We thus compared neuromuscular junctions from adult Rab3A(-/-) mutant mice with those from wild-type mice with respect to: (a) the basic electrophysiological correlates of neurotransmitter release at different stimulation frequencies, and (b) the actions of exogenous and endogenous adenosine on neurotransmitter release in normal calcium solutions. Neither the spontaneous quantal release of acetylcholine (ACh) nor basal evoked ACh release (0.05 Hz) differed between the mutant and wild-type mice. At 50-100 Hz stimulation (10-19 stimuli), facilitation of release was observed in the mutant mice but not in wild-type, followed by a depression of ACh release in both strains. ACh release at the end of the stimulus train in the mutant mouse was approximately double that of the wild-type mouse. The threshold concentration for inhibition of ACh release by exogenous adenosine was over 20-fold lower in the mutant mouse than in the wild-type mouse. The adenosine A(1) receptor antagonist 8-cyclopentyltheophylline (CPT) increased ACh release (0.05-1 Hz stimulation) in the mutant mouse under conditions in which it had no effect in the wild-type mouse. CPT had no effect on the pattern of responses recorded during repetitive stimulation in either strain. The results suggest that Rab3A reduces the potency of adenosine as an endogenous mediator of neuromuscular depression.
Rab3a is a small GTP binding protein associated with presynaptic vesicles that is thought to regulate vesicle targeting to active zones. Although this rab3a function implies that vesicle docking and action potential-evoked release might be inhibited in rab3a gene-deleted synapses, such inhibition has never been demonstrated. To investigate vesicle docking at the neuromuscular junction of rab3a gene-deleted (rab3a(-)) mice, we performed electron microscopy analysis of the diaphragm slow-fatigue (type I) synapses. We found a significant (26%) reduction in the number of vesicles docked to the presynaptic membrane in rab3a(-) terminals, although intraterminal vesicles were not affected. Aiming to detect possible changes in quantal release due to rab3a gene deletion, we minimized the variability between preparations employing focal recordings of synaptic responses from visualized type I endplates. We found a significant decrease in both evoked (27% reduction in quantal content) and spontaneous (28% reduction in mini frequency) quantal release. The decrease in the evoked release produced by rab3a deletion was most pronounced at reduced extracellular Ca(2+) concentrations (over 50% decrease at 0.5 and 0.2 mM Ca(2+)). By manipulating extracellular calcium, we demonstrated that calcium cooperativity is not altered in rab3a(-) synapses, however calcium sensitivity of quantal release is affected. Thus, we demonstrated that rab3a positively regulates docking and basal quantal release at the mouse neuromuscular junction. This result is consistent with the proposed role of rab3a in trafficking and targeting vesicles to the active zones.
Rab3A is a small Ras-like GTPase critical for membrane traffic. Although the functions of Rab3A have been reported in several cancers, the roles of Rab3A in hepatocellular carcinoma (HCC) have never been determined. To investigate the potential roles of Rab3A in HCC progression, we first determined Rab3A levels in HCC tissues and observed upregulated mRNA and protein levels of Rab3A in most tumor tissues. However, in vitro data showed that decreasing Rab3A in most HCC cell lines conferred no significant effects and overexpressing Rab3A in PLC/PRF/5 cells even inhibited migration and invasion. Meanwhile, the upregulation of Rab3A in HCC patients did not correlate with metastasis or overall survival of HCC patients. These contradict data suggested that Rab3A might act as metastatic suppressor and its effects might be attenuated in most HCC cells. Further experiments revealed that O-GlcNAcylation on Rab3A was key for attenuating Rab3A-mediated effects by regulating its GTP-binding activity, and verified the effects of Rab3A and its aberrant O-GlcNAcylation on HCC metastasis in vitro and in vivo. We also found that Rab3A and its O-GlcNAcylation had opposite roles in mitochondria oxidative phosphorylation (mtOXPHOS), and their functions on HCC metastasis were partially depended on their effects on metabolic reprogramming.
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