The munc13-4–rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane

Elstak, Edo; Neeft, Maaike; Nehme, Nadine T.; Voortman, Jarno; Cheung, Marc; Goodarzifard, M.; Gerritsen, Hans C.; Henegouwen, Paul M.P. van Bergen en; Callebaut, Isabelle; Basile, Geneviève de Saint; Sluijs, Peter van der

doi:10.1182/blood-2011-02-339523

Cited by 119 publications

(129 citation statements)

References 51 publications

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“…2B). Moreover, because the involvement of Rab27B in regulating mast cell exocytosis is well established (33)(34)(35), the CA mutant of this Rab also served to validate our experimental setting. Expression of CA Rab27B significantly reduced NPYmRFP release compared with release from control GFPexpressing cells (Fig.…”

Section: Development Of a Quantitative Screening Methodologymentioning

confidence: 92%

Decoding the Regulation of Mast Cell Exocytosis by Networks of Rab GTPases

Azouz

Matsui

Fukuda

et al. 2012

The Journal of Immunology

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Exocytosis is a key event in mast cell functions. By this process, mast cells release inflammatory mediators, contained in secretory granules (SGs), which play important roles in immunity and wound healing but also provoke allergic and inflammatory responses. The mechanisms underlying mast cell exocytosis remained poorly understood. An essential step toward deciphering the mechanisms behind exocytosis is the identification of the cellular components that regulate this process. Because Rab GTPases regulate specific trafficking pathways, we screened 44 Rabs for their functional impacts on exocytosis triggered by the FcεRI or combination of Ca2+ ionophore and phorbol ester. Because exocytosis involves the continuous reorganization of the actin cytoskeleton, we also repeated our screen in the presence of cytochalasin D that inhibits actin polymerization. In this paper, we report on the identification of 30 Rabs as regulators of mast cell exocytosis, the involvement of 26 of which has heretofore not been recognized. Unexpectedly, these Rabs regulated exocytosis in a stimulus-dependent fashion, unless the actin skeleton was disrupted. Functional clustering of the identified Rabs suggested their classification as Rabs involved in SGs biogenesis or Rabs that control late steps of exocytosis. The latter could be further divided into Rabs that localize to the SGs and Rabs that regulate transport from the endocytic recycling compartment. Taken together, these findings unveil the Rab networks that control mast cell exocytosis and provide novel insights into their mechanisms of action.

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Section: Development Of a Quantitative Screening Methodologymentioning

confidence: 92%

Decoding the Regulation of Mast Cell Exocytosis by Networks of Rab GTPases

Azouz

Matsui

Fukuda

et al. 2012

The Journal of Immunology

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“…However, there have been significantly fewer studies conducted based on immune cell exocytosis (36,40,43,44).…”

Section: Discussionmentioning

confidence: 99%

Crucial role of the hydrophobic pocket region of Munc18 protein in mast cell degranulation

Bin

Jung

Piggott

et al. 2013

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

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The function of the Munc18-1 protein hydrophobic pocket, which interacts with the syntaxin-1 N-terminal peptide, has been highly controversial in neurosecretion. Recent analysis of patients with familial hemophagocytic lymphohistiocytosis type 5 has identified the E132A mutation in the hydrophobic pocket of Munc18-2, prompting us to examine the role of this region in the context of immune cell secretion. Double knockdown of Munc18-1 and Munc18-2 in RBL-2H3 mast cells eliminates both IgE-dependent and ionomycin-induced degranulation and causes a significant reduction in syntaxin-11 without altering expressions of the other syntaxin isoforms examined. These phenotypes were effectively rescued on reexpression of wild-type Munc18-1 or Munc18-2 but not the mutants (F115E, E132A, and F115E/E132A) in the hydrophobic pocket of Munc18. In addition, these mutants show that they are unable to directly interact with syntaxin-11, as tested through protein interaction experiments. Our results demonstrate the crucial roles of the hydrophobic pocket of Munc18 in mast cell degranulation, which include the regulation of syntaxin-11. We also suggest that the functional importance of this region is significantly different between neuronal and immune cell exocytosis.membrane fusion | FHL5

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“…11,12 (Mammalian Uncoordinated) Munc13-4 was coimmunoprecipitated with Rab-27a and evaluated through WB. 13 …”

Section: Methodsmentioning

confidence: 99%

Mutation of FAS, XIAP, and UNC13D Genes in a Patient With a Complex Lymphoproliferative Phenotype

Boggio¹,

Melensi

Dianzani

et al. 2013

Pediatrics

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This article presents a case report for a child presenting with mixed clinical features of autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis (FHL), and X-linked lymphoproliferative (XLP) disease. From 6 months, he exhibited splenomegaly and lymphoadenopathy and from 4 years, he showed recurrent severe autoimmune hemocytopenia and sepsislike bouts of fever, from which he eventually died at the age of 12. Intriguingly, the patient carried mutations in FAS, XIAP, and UNC13D genes, which are involved in ALPS, XLP disease, and FHL, respectively. These mutations were inherited from the mother, who had rheumatoid arthritis but no signs of ALPS. A role for other modifying genes was suggested by the finding that the healthy father exhibited defective Fas function, without mutation of the FAS gene, and had transmitted to the patient an osteopontin (OPN) gene variant previously associated with ALPS. Therefore, several genes might influence the disease outcome in this family. In vitro analyses revealed that the FAS and the XIAP mutations decreased expression of the corresponding proteins, and the UNC13D mutation decreased granule secretion and Munc interaction with Rab27a. These findings suggest that overlap may exist between ALPS, FHL, and XLP disease, in accordance with the notion that FHL and XLP disease are due to defective natural killer (NK)/NK T-cell function, which involves Fas. Therefore, we propose that NK cell defects should be evaluated in patients with ALPS-like characteristics, and hematopoietic stem cell transplantation should be considered in individuals with severe refractory cytopenia and FHL-like manifestations. Pediatrics 2013;132:e1052-e1058 AUTHORS:

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The munc13-4–rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane

Cited by 119 publications

References 51 publications

Decoding the Regulation of Mast Cell Exocytosis by Networks of Rab GTPases

Decoding the Regulation of Mast Cell Exocytosis by Networks of Rab GTPases

Crucial role of the hydrophobic pocket region of Munc18 protein in mast cell degranulation

Mutation of FAS, XIAP, and UNC13D Genes in a Patient With a Complex Lymphoproliferative Phenotype

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