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

PKCδ-dependent phosphorylation of the SNARE inhibitor tomosyn reduces mast cell degranulation. The right partner for secretion Basophils and mast cells are immune cells that initiate allergic reactions and participate in host defense by releasing intracellular granules that contain proteases, lipid mediators, cytokines, and histamine. Degranulation requires the fusion of secretory granules with the plasma membrane, a process that is tightly controlled by SNARE family proteins. Madera-Salcedo et al. noted that, in basophils of allergy patients, serum IgE concentration correlated with the abundance of tomosyn, an inhibitor of SNARE activity. PKCδ-dependent phosphorylation of tomosyn caused it to swap its SNARE protein binding partner. Inhibition or loss of PKC increased mast cell degranulation. The authors suggest that the IgE-correlated expression of tomosyn may function as a feedback loop to limit mast cell degranulation and allergic symptoms in patients. 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.