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


ABSTRACT: Cross-linking of mast cell (MC) IgE receptors (Fc?RI) 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 Fc?RI-initiated signaling pathways, or microtubule reorganization upon Fc?RI 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.

SUBMITTER: Munoz I 

PROVIDER: S-EPMC5084650 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Munoz Isabelle I   Munoz Isabelle I   Danelli Luca L   Claver Julien J   Goudin Nicolas N   Kurowska Mathieu M   Madera-Salcedo Iris Karina IK   Huang Jian-Dong JD   Fischer Alain A   González-Espinosa Claudia C   de Saint Basile Geneviéve G   Blank Ulrich U   Ménasché Gaël G  

The Journal of cell biology 20161001 2


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 anaphyla  ...[more]

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