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Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex

Cross-linking of mast cell (MC) IgE receptors (FcεRI) triggers degranulation of secretory granules (SGs) and the release of many allergic and inflammatory mediators. Although degranulation depends crucially on microtubule dynamics, the molecular machinery that couples SGs to microtubule-dependent tr...

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Autores principales: Munoz, Isabelle, Danelli, Luca, Claver, Julien, Goudin, Nicolas, Kurowska, Mathieu, Madera-Salcedo, Iris Karina, Huang, Jian-Dong, Fischer, Alain, González-Espinosa, Claudia, de Saint Basile, Geneviéve, Blank, Ulrich, Ménasché, Gaël
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084650/
https://www.ncbi.nlm.nih.gov/pubmed/27810912
http://dx.doi.org/10.1083/jcb.201605073
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author Munoz, Isabelle
Danelli, Luca
Claver, Julien
Goudin, Nicolas
Kurowska, Mathieu
Madera-Salcedo, Iris Karina
Huang, Jian-Dong
Fischer, Alain
González-Espinosa, Claudia
de Saint Basile, Geneviéve
Blank, Ulrich
Ménasché, Gaël
author_facet Munoz, Isabelle
Danelli, Luca
Claver, Julien
Goudin, Nicolas
Kurowska, Mathieu
Madera-Salcedo, Iris Karina
Huang, Jian-Dong
Fischer, Alain
González-Espinosa, Claudia
de Saint Basile, Geneviéve
Blank, Ulrich
Ménasché, Gaël
author_sort Munoz, Isabelle
collection PubMed
description Cross-linking of mast cell (MC) IgE receptors (FcεRI) triggers degranulation of secretory granules (SGs) and the release of many allergic and inflammatory mediators. Although degranulation depends crucially on microtubule dynamics, the molecular machinery that couples SGs to microtubule-dependent transport is poorly understood. In this study, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in hematopoietic cells are less sensitive to IgE-mediated, passive, systemic anaphylaxis. After IgE-induced stimulation, bone marrow–derived MCs from Kif5b knockout mice exhibited a marked reduction in SG translocation toward the secretion site. In contrast, a lack of Kif5b did not affect cytokine secretion, early FcεRI-initiated signaling pathways, or microtubule reorganization upon FcεRI stimulation. We identified Slp3 as the critical effector linking kinesin-1 to Rab27b-associated SGs. Kinesin-1 recruitment to the Slp3/Rab27b effector complex was independent of microtubule reorganization but occurred only upon stimulation requiring phosphatidylinositol 3-kinase (PI3K) activity. Our findings demonstrate that PI3K-dependent formation of a kinesin-1/Slp3/Rab27b complex is critical for the microtubule-dependent movement of SGs required for MC degranulation.
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spelling pubmed-50846502017-04-24 Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex Munoz, Isabelle Danelli, Luca Claver, Julien Goudin, Nicolas Kurowska, Mathieu Madera-Salcedo, Iris Karina Huang, Jian-Dong Fischer, Alain González-Espinosa, Claudia de Saint Basile, Geneviéve Blank, Ulrich Ménasché, Gaël J Cell Biol Research Articles Cross-linking of mast cell (MC) IgE receptors (FcεRI) triggers degranulation of secretory granules (SGs) and the release of many allergic and inflammatory mediators. Although degranulation depends crucially on microtubule dynamics, the molecular machinery that couples SGs to microtubule-dependent transport is poorly understood. In this study, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in hematopoietic cells are less sensitive to IgE-mediated, passive, systemic anaphylaxis. After IgE-induced stimulation, bone marrow–derived MCs from Kif5b knockout mice exhibited a marked reduction in SG translocation toward the secretion site. In contrast, a lack of Kif5b did not affect cytokine secretion, early FcεRI-initiated signaling pathways, or microtubule reorganization upon FcεRI stimulation. We identified Slp3 as the critical effector linking kinesin-1 to Rab27b-associated SGs. Kinesin-1 recruitment to the Slp3/Rab27b effector complex was independent of microtubule reorganization but occurred only upon stimulation requiring phosphatidylinositol 3-kinase (PI3K) activity. Our findings demonstrate that PI3K-dependent formation of a kinesin-1/Slp3/Rab27b complex is critical for the microtubule-dependent movement of SGs required for MC degranulation. The Rockefeller University Press 2016-10-24 /pmc/articles/PMC5084650/ /pubmed/27810912 http://dx.doi.org/10.1083/jcb.201605073 Text en © 2016 Munoz et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Munoz, Isabelle
Danelli, Luca
Claver, Julien
Goudin, Nicolas
Kurowska, Mathieu
Madera-Salcedo, Iris Karina
Huang, Jian-Dong
Fischer, Alain
González-Espinosa, Claudia
de Saint Basile, Geneviéve
Blank, Ulrich
Ménasché, Gaël
Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex
title Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex
title_full Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex
title_fullStr Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex
title_full_unstemmed Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex
title_short Kinesin-1 controls mast cell degranulation and anaphylaxis through PI3K-dependent recruitment to the granular Slp3/Rab27b complex
title_sort kinesin-1 controls mast cell degranulation and anaphylaxis through pi3k-dependent recruitment to the granular slp3/rab27b complex
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084650/
https://www.ncbi.nlm.nih.gov/pubmed/27810912
http://dx.doi.org/10.1083/jcb.201605073
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