Phosphatidylinositol-3-Kinase C2B and TRIM27 Function to Positively and Negatively Regulate IGE Receptor Activation of Mast Cells

Abstract

Cross linking of the IgE receptor (FceRI) on mast cells plays a critical role in IgE-dependent allergy including allergic rhinitis, asthma, anaphylaxis, and immediate type hypersensitivity reactions. Previous studies have demonstrated that the K+ channel, KCa3.1, plays a critical role in IgE-stimulated Ca2+ entry and degranulation in both human and mouse mast cells. We now show that the class II phosphatidylinositol 3 kinase C2b (PI3KC2b) is necessary for FceRI stimulated activation of KCa3.1, Ca2+ influx, cytokine production and degranulation of bone marrow derived mast cells (BMMC). In addition, we found that the E3 ubiquitin ligase, tripartite motif containing protein 27 (TRIM27), negatively regulates FceRI activation of KCa3.1, and downstream signaling by ubiquitinating and inhibiting PI3KC2b.TRIM27-/- mice are also more susceptible in vivo to acute anaphylaxis. These findings identify TRIM27 as an important negative regulator of mast cells in vivo, and suggests that PI3KC2b is a potential new pharmacologic target to treat IgE mediated disease.