Molecular mechanism of IgE-mediated FcεRI activation

Nature. 2025 Jan;637(8045):453-460. doi: 10.1038/s41586-024-08229-8. Epub 2024 Oct 23.

Abstract

Allergic diseases affect more than a quarter of individuals in industrialized countries, and are a major public health concern1,2. The high-affinity Fc receptor for immunoglobulin E (FcεRI), which is mainly present on mast cells and basophils, has a crucial role in allergic diseases3-5. Monomeric immunoglobulin E (IgE) binding to FcεRI regulates mast cell survival, differentiation and maturation6-8. However, the underlying molecular mechanism remains unclear. Here we demonstrate that prior to IgE binding, FcεRI exists mostly as a homodimer on human mast cell membranes. The structure of human FcεRI confirms the dimeric organization, with each promoter comprising one α subunit, one β subunit and two γ subunits. The transmembrane helices of the α subunits form a layered arrangement with those of the γ and β subunits. The dimeric interface is mediated by a four-helix bundle of the α and γ subunits at the intracellular juxtamembrane region. Cholesterol-like molecules embedded within the transmembrane domain may stabilize the dimeric assembly. Upon IgE binding, the dimeric FcεRI 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 FcεRI dimer-to-monomer transition. Collectively, our study reveals the mechanism of antigen-independent, IgE-mediated FcεRI activation.

MeSH terms

  • Animals
  • Basophils* / immunology
  • Basophils* / metabolism
  • Cell Membrane* / metabolism
  • Cholesterol / metabolism
  • Early Growth Response Protein 1 / chemistry
  • Early Growth Response Protein 1 / metabolism
  • Humans
  • Immunoglobulin E* / chemistry
  • Immunoglobulin E* / immunology
  • Immunoglobulin E* / metabolism
  • Male
  • Mast Cells* / immunology
  • Mast Cells* / metabolism
  • Models, Molecular
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Multimerization*
  • Protein Subunits* / chemistry
  • Protein Subunits* / metabolism
  • Rats
  • Receptors, IgE* / chemistry
  • Receptors, IgE* / metabolism

Substances

  • Receptors, IgE
  • Immunoglobulin E
  • Protein Subunits
  • Early Growth Response Protein 1
  • Cholesterol