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 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.
Laboratory of Normal and Pathological Homeostasis of the Immune System, Institut National de la Santé et de la Recherche Médicale, UMR1163, F-75015 Paris, France.|Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, F-75015 Paris, France.
Isabelle
http://orcid.org/0000-0002-1754-5344
I
Munoz
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149; Centre de Recherche sur l'Inflammation, Centre National de la Recherche Scientifique, Equipe de Recherche Labelisé 8252; Inflamex Laboratory of Excellence, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France.
Luca
http://orcid.org/0000-0003-1222-0732
L
Danelli
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149; Centre de Recherche sur l'Inflammation, Centre National de la Recherche Scientifique, Equipe de Recherche Labelisé 8252; Inflamex Laboratory of Excellence, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France.
Julien
J
Claver
Cell Imaging Facility, Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, F-75015 Paris, France.
Nicolas
http://orcid.org/0000-0002-3967-4016
N
Goudin
Laboratory of Normal and Pathological Homeostasis of the Immune System, Institut National de la Santé et de la Recherche Médicale, UMR1163, F-75015 Paris, France.|Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, F-75015 Paris, France.
Mathieu
M
Kurowska
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149; Centre de Recherche sur l'Inflammation, Centre National de la Recherche Scientifique, Equipe de Recherche Labelisé 8252; Inflamex Laboratory of Excellence, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France.
Iris Karina
http://orcid.org/0000-0002-0741-9248
IK
Madera-Salcedo
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Jian-Dong
JD
Huang
Laboratory of Normal and Pathological Homeostasis of the Immune System, Institut National de la Santé et de la Recherche Médicale, UMR1163, F-75015 Paris, France.|Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, F-75015 Paris, France.|Immunology and Pediatric Hematology Department, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, F-75015 Paris, France.|Collège de France, F-75005 Paris, France.
Alain
http://orcid.org/0000-0003-4025-5983
A
Fischer
Departamento de Farmacobiología, Cinvestav, Sede Sur, 14330 Mexico City, Mexico.
Claudia
http://orcid.org/0000-0001-7332-3829
C
González-Espinosa
Laboratory of Normal and Pathological Homeostasis of the Immune System, Institut National de la Santé et de la Recherche Médicale, UMR1163, F-75015 Paris, France.|Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, F-75015 Paris, France.
Geneviéve
G
de Saint Basile
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149; Centre de Recherche sur l'Inflammation, Centre National de la Recherche Scientifique, Equipe de Recherche Labelisé 8252; Inflamex Laboratory of Excellence, Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France.
Ulrich
http://orcid.org/0000-0002-2661-2983
U
Blank
Laboratory of Normal and Pathological Homeostasis of the Immune System, Institut National de la Santé et de la Recherche Médicale, UMR1163, F-75015 Paris, France gael.menasche@inserm.fr.|Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, F-75015 Paris, France.
Gaël
G
Ménasché
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015550:Cell Degranulation; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D016547:Kinesins / Q000378:metabolism*; D008407:Mast Cells / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D018345:Mice, Knockout; D018715:Microscopy, Video; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D017455:Receptors, IgE / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
D016207:Cytokines; D016547:Kinesins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D017455:Receptors, IgE; D020691:rab GTP-Binding Proteins; C461699:Stoml3 protein, mouse; C475469:Kif5b protein, mouse; C512958:Rab27b protein, mouse