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Molecular mechanism of IgE-mediated FcεRI activation
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Journal Article
Molecular mechanism of IgE-mediated FcεRI activation
2025
Overview
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 (FcεRI), which is mainly present on mast cells and basophils, has a crucial role in allergic diseases
3
,
4
–
5
. Monomeric immunoglobulin E (IgE) binding to FcεRI regulates mast cell survival, differentiation and maturation
6
,
7
–
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.
Biochemical and structural studies of the Fc immunoglobulin E receptor show that it exists as a homodimer on mast cell membranes, but dissociates upon IgE binding, exposing immunoreceptor tyrosine-based activation motifs that enable downstream effector activation.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 82/80
/ Animals
/ Antigens
/ Binding
/ Dimers
/ Early Growth Response Protein 1 - chemistry
/ Early Growth Response Protein 1 - metabolism
/ Early Growth Response Protein 3
/ Helices
/ Humanities and Social Sciences
/ Humans
/ Immunoglobulin E - chemistry
/ Immunoglobulin E - immunology
/ Immunoglobulin E - metabolism
/ Kinases
/ Male
/ Monocyte chemoattractant protein 1
/ Promoter Regions, Genetic - genetics
/ Protein Subunits - chemistry
/ Protein Subunits - metabolism
/ Rats
/ Science
