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Madera-Salcedo, Iris K; Danelli, Luca; Tiwari, Neeraj; Dema, Barbara; Pacreau, Emeline; Vibhushan, Shamila; Birnbaum, Joelle; Agabriel, Chantal; Liabeuf, Valerie; Klingebiel, Caroline; Menasche, Gael; Macias-Silva, Marina; Benhamou, Marc; Charles, Nicolas; Gonzalez-Espinosa, Claudia; Vitte, Joana; Blank, Ulrich (2018)

TOMOSYN FUNCTIONS AS A PKC DELTA-REGULATED FUSION CLAMP IN MAST CELL DEGRANULATION

Sci Signal 11(537):
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Soluble -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.