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Tomosyn functions as a PKCδ-regulated fusion clamp in mast cell degranulation

Iris Madera-Salcedo 1, 2 Luca Danelli 1, 2 Neeraj Tiwari 1, 2 Barbara Dema 1, 2 Emeline Pacreau 1, 2 Shamila Vibhushan 1, 2 Joëlle Birnbaum 3 Chantal Agabriel 4 Valérie Liabeuf 3 Caroline Klingebiel 5 Gaël Ménasché 6, 7 Marina Macias-Silva 8 Marc Benhamou 1, 2 Nicolas Charles 1, 2 Claudia González-Espinosa 9 Joana Vitte 10, 11 Ulrich Blank 1, 2, *
* Corresponding author
1 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
2 Faculté de Médecine Xavier Bichat - Laboratoire d'Excellence Inflamex [Paris]
3 Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM]
4 Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM]
5 Laboratoire BIOPLUS [Marseille, France]
6 Equipe Inserm U1163 - Normal and pathological homeostasis of the immune system
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
7 USPC - Université Sorbonne Paris Cité
8 Instituto de Fisiología Celular [México City, México]
9 Departamento de Farmacobiología [Mexico City, Mexico]
10 LAI - Adhésion et Inflammation
11 IHU Méditerranée Infection - Laboratoire d’Immunologie [Hôpital La Timone - APHM]
Abstract : Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family proteins mediate membrane fusion critical for vesicular transport and cellular secretion. Mast cells rely on SNARE-mediated membrane fusion for degranulation stimulated by crosslinking of immunoglobulin E (IgE) bound to the Fcε receptor (FcεRI). We investigated the mechanisms downstream of receptor activation that control degranulation. We found that the SNARE binding protein tomosyn-1 (also known as STXBP5) inhibited FcεRI-stimulated degranulation of mast cells. After mast cell activation, tomosyn-1 was phosphorylated on serine and threonine residues, dissociated from the SNARE protein syntaxin 4 (STX4), and associated with STX3. We identified PKCδ as the major kinase required for tomosyn-1 threonine phosphorylation and for regulation of the interaction with STXs. Incubation with high IgE concentrations increased tomosyn-1 abundance in cultured mast cells. Similarly, in basophils from allergic patients with high amounts of serum IgE, the abundance of tomosyn-1 was increased as compared to that in patients with normal IgE concentrations. Our findings identified tomosyn-1 as an inhibitor of mast cell degranulation that required PKCδ to switch its interaction with STX partners during fusion. We suggest that the IgE-mediated increase in tomosyn-1 abundance in allergic patients may represent a counterregulatory mechanism to limit disease development. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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CNRS | UNIV-PARIS5 | UNIV-AMU | UNIV-PARIS7 | USPC

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Iris Madera-Salcedo, Luca Danelli, Neeraj Tiwari, Barbara Dema, Emeline Pacreau, et al.. Tomosyn functions as a PKCδ-regulated fusion clamp in mast cell degranulation. Science Signaling, American Association for the Advancement of Science, 2018, 11 (537), pp.eaan4350. ⟨10.1126/scisignal.aan4350⟩. ⟨inserm-02323254⟩

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