Journal
JOURNAL OF CELL BIOLOGY
Volume 215, Issue 2, Pages 203-216Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201605073
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Funding
- Institut National de la Sante et de la Recherche Medicale
- French National Research Agency [ANR-12-BSV1-0020-01, ANR HLH-cytotox]
- International collaboration grant from L'Agence National de la Recherche France [ANR-12-ISV3-0006-01]
- Conacyt Mexico [ANR188565]
- ARC Foundation [PJA20131200047]
- European Research Council (PIDImmun) [249816]
- Societe Francaise d'Allergologie (grant SFA-D.A. Moneret-Vautrin)
- Investissements d'Avenir program (Sorbonne Paris Cite, Laboratoire d'excellence INF LAMEX) [ANR-11-IDEX-0005-02]
- Ministere de l'Education Nationale de la Recherche et de la Technologie
- Imagine Foundation
- French government's Investissementd 'Avenirprogram [ANR-10-IAHU-01]
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV1-0020] Funding Source: Agence Nationale de la Recherche (ANR)
- European Research Council (ERC) [249816] Funding Source: European Research Council (ERC)
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Cross-linking of mast cell (MC) IgE receptors (Fc epsilon 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 epsilon RI-initiated signaling pathways, or microtubule reorganization upon Fc epsilon 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/S1p3/Rab27b complex is critical for the microtubule-dependent movement of SGs required for MC degranulation.
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