Tomosyn functions as a PKC{delta}-regulated fusion clamp in mast cell degranulation

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 Fc receptor (FcRI). 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 FcRI-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 PKC 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 PKC 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.

Source: Signal Transduction Knowledge Environment - July 3, 2018 Category: Science Authors: Madera-Salcedo, I. K., Danelli, L., Tiwari, N., Dema, B., Pacreau, E., Vibhushan, S., Birnbaum, J., Agabriel, C., Liabeuf, V., Klingebiel, C., Menasche, G., Macias-Silva, M., Benhamou, M., Charles, N., Gonzalez-Espinosa, C., Vitte, J., Blank, U. Tags: STKE Research Articles Source Type: news