Munc13-4 Is a GTP-Rab27-binding Protein Regulating Dense Core Granule Secretion in Platelets

Shirakawa, Ryutaro; Higashi, Tomohito; Tabuchi, Arata; Yoshioka, Akira; Nishioka, Hiroaki; Fukuda, Mitsunori; Kita, Toru; Horiuchi, Hisanori

doi:10.1074/jbc.m309426200

Cited by 197 publications

(196 citation statements)

References 57 publications

(61 reference statements)

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“…For example, the affinity of Munc13-4 for Rab27a is reported to be much stronger than for Rab27b. (21) This trend also was observed in the present results of the His-tag pull-down assay (Fig. 4C); therefore, the contribution of Rab27b to the mechanism involving Munc13-4, Slp5, and probably Slp4-a is lower than that of Rab27a, raising the possibility that the function of Rab27b in stimulation-dependent RANKL release also may be coordinated with other effector molecules.…”

Section: Discussionsupporting

confidence: 84%

“…Rab proteins in their active form (GTP-bound form) are carried on the surfaces of cargo vesicles and function as markers for the transport and fusion of these vesicles with the acceptor membrane (17) by associating with effector molecules that mediate their interaction with motor proteins, (18) phospholipids, or soluble NSF attachment protein receptor (SNARE) components. (19) Rab27a, which is expressed in many types of secretory organs, is reported to be involved in secretion from lysosomal organelles such as secretory granules in insulin-secreting cells, (20) dense granules in platelets, (21) dense-core vesicles in neuroendocrine cells, (22) melanosomes in melanocytes, (23) and lytic granules in cytotoxic T-lymphocytes (CTLs). (24) Several Rab27a effector molecules also have been identified.…”

Section: Introductionmentioning

confidence: 99%

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Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Kariya

Honma

Hanamura

et al. 2010

Journal of Bone and Mineral Research

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The quantity of the receptor activator of NF-kB ligand (RANKL) expressed at the cell surface of osteoblastic cells is an important factor regulating osteoclast activation. Previously, RANKL was found to be localized to secretory lysosomes in osteoblastic cells and to translocate to the cell surface in response to stimulation with RANK-Fc-conjugated beads. However, the in vivo significance of stimulation-dependent RANKL release has not been elucidated. In this study we show that small GTPases Rab27a and Rab27b are involved in the stimulation-dependent RANKL release pathway in osteoblastic cells. Suppression of either Rab27a or Rab27b resulted in a marked reduction in RANKL release after stimulation. Slp4-a, Slp5, and Munc13-4 acted as effector molecules that coordinated Rab27a/b activity in this pathway. Suppression of Rab27a/b or these effector molecules did not inhibit accumulation of RANKL in lysosomal vesicles around the stimulated sites but did inhibit the fusion of these vesicles to the plasma membrane. In osteoblastic cells, suppression of the effector molecules resulted in reduced osteoclastogenic ability. Furthermore, Jinx mice, which lack a functional Munc13-4 gene, exhibited a phenotype characterized by increased bone volume near the tibial metaphysis caused by low bone resorptive activity. In conclusion, stimulation-dependent RANKL release is mediated by Rab27a/b and their effector molecules, and this mechanism may be important for osteoclast activation in vivo. ß

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Kariya

Honma

Hanamura

et al. 2010

Journal of Bone and Mineral Research

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“…In peripheral tissues, Rab27 has been studied due to its role in Griscelli syndrome. The immunodeficiency of Griscelli syndrome patients is due to a defect in lytic granule exocytosis from cytotoxic T-cells and may be mediated by effectors such as Munc13-4 and granuphilin Goishi et al, 2004;Shirakawa et al, 2004;Torii et al, 2004;Yamamoto et al, 2004;Neeft et al, 2005). In addition, Rab27 plays a role in exocytosis of dense core granules from both endocrine and exocrine cells (Chen et al, 2003;Fukuda, 2003b;Izumi et al, 2003;Chen et al, 2004;Goishi et al, 2004;Imai et al, 2004;Matsumoto et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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

Mahoney

Liu

Itoh

et al. 2006

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155

217

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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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“…Previous studies have demonstrated that Munc13-4 is essential for lytic granule exocytosis at the immunological synapse (9), neutrophil granule secretion (3), and platelet-dense granule exocytosis (11). Based on pulldown studies and molecular interaction assays, it was proposed that Munc13-4 is a specific effector of the small GTPase Rab27a (11,12), which also plays an important role in the regulation of secretory lysosome exocytosis (13). Despite shared roles in regulating common secretory pathways, it is unclear whether they act together to regulate the same steps during exocytosis.…”

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confidence: 99%

Munc13-4 Restricts Motility of Rab27a-expressing Vesicles to Facilitate Lipopolysaccharide-induced Priming of Exocytosis in Neutrophils

Johnson¹,

Hong²,

Monfregola³

et al. 2011

Journal of Biological Chemistry

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LPS is an efficient sensitizer of the neutrophil exocytic response to a second stimulus. Although neutrophil exocytosis in response to pathogen-derived molecules plays an important role in the innate immune response to infections, the molecular mechanism underlying LPS-dependent regulation of neutrophil exocytosis is currently unknown. The small GTPase Rab27a and its effector Munc13-4 regulate exocytosis in hematopoietic cells. Whether Rab27a and Munc13-4 modulate discrete steps or the same steps during exocytosis also remains unknown. Here, using Munc13-4-and Rab27a-deficient neutrophils, we analyzed the mechanism of lipopolysaccharide-dependent vesicular priming to amplify exocytosis of azurophilic granules. We found that both Munc13-4 and Rab27a are necessary to mediate LPS-dependent priming of exocytosis. However, we show that LPS-induced mobilization of a small population of readily releasable vesicles is a Munc13-4-dependent but Rab27a-independent process. LPS-induced priming regulation could not be fully explained by secretory organelle maturation as the redistribution of the secretory proteins Rab27a or Munc13-4 in response to LPS treatment was minimal. Using total internal reflection fluorescence microscopy and a novel mouse model expressing EGFP-Rab27a under the endogenous Rab27a promoter but lacking Munc13-4, we demonstrate that Munc13-4 is essential for the mechanism of LPS-dependent exocytosis in neutrophils and unraveled a novel mechanism of vesicular dynamics in which Munc13-4 restricts motility of Rab27a-expressing vesicles to facilitate lipopolysaccharideinduced priming of exocytosis.

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Munc13-4 Is a GTP-Rab27-binding Protein Regulating Dense Core Granule Secretion in Platelets

Cited by 197 publications

References 57 publications

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

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

Munc13-4 Restricts Motility of Rab27a-expressing Vesicles to Facilitate Lipopolysaccharide-induced Priming of Exocytosis in Neutrophils

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