Molecular mechanism of IgE-mediated FcεRI activation

Allergic diseases affect more than a quarter of individuals in industrialized countries, and are a major public health concern(1,2). The high-affinity Fc receptor for immunoglobulin E (Fc epsilon RI), which is mainly present on mast cells and basophils, has a crucial role in allergic diseases(3-5). Monomeric immunoglobulin E (IgE) binding to Fc epsilon RI regulates mast cell survival, differentiation and maturation(6-8). However, the underlying molecular mechanism remains unclear. Here we demonstrate that prior to IgE binding, Fc epsilon RI exists mostly as a homodimer on human mast cell membranes. The structure of human Fc epsilon RI confirms the dimeric organization, with each promoter comprising one a subunit, one beta subunit and two gamma subunits. The transmembrane helices of the alpha subunits form a layered arrangement with those of the. and beta subunits. The dimeric interface is mediated by a four-helix bundle of the alpha and gamma subunits at the intracellular juxtamembrane region. Cholesterol-like molecules embedded within the transmembrane domain may stabilize the dimeric assembly. Upon IgE binding, the dimeric FceRI dissociates into two protomers, each of which binds to an IgE molecule. This process elicits transcriptional activation of Egr1, Egr3 and Ccl2 in rat basophils, which can be attenuated by inhibiting the Fc epsilon RI dimer-to-monomer transition. Collectively, our study reveals the mechanism of antigen-independent, IgE-mediated Fc epsilon RI activation.