p28, a Novel IgE Receptor-associated Protein, Is a Sensor of Receptor Occupation by Its Ligand in Mast Cells

Abstract

Mast cells express the high affinity receptor for IgE (FcεRI). Aggregation of this receptor by IgE and antigen leads to a signaling cascade resulting in the secretion of histamine, in the synthesis of other pro-inflammatory mediators such as leukotrienes and prostaglandins, and in the production of various cytokines, all of which participate in the development of the allergic reaction. In the last years, growing evidence accumulated that binding of IgEs to FcεRI in itself induces active signals leading to mast cell survival, increased expression of FcεRI, transient induction of histidine decarboxylase synthesis, and increased cell adhesion. The mechanisms underlying monomeric IgE signaling in the absence of receptor aggregation are still poorly understood. Here, we show that a protein of 28 kDa (p28) is physically and constitutively associated with FcεRI in mast cells. Co-immunoprecipitation studies from 125I surface-labeled cells demonstrated that this association involves at least 50% of membrane-expressed FcεRI. After the addition of monomeric IgE to the cells, the p28·FcεRI complex dissociates almost completely in less than 2 min. This dissociation is temperature-sensitive and is not due to the recruitment of additional proteins to the complex. Stripping bound IgE from the cells by acidic treatment promotes a rapid reassociation between p28 and FcεRI. Altogether, these data are consistent with a conformational regulation of the complex. Thus, p28 is a sensor for FcεRI occupation by IgE on mast cells, and its dissociation from the receptor could represent an early step of monomeric IgE signaling.