Identification of redundancy between human FcεRIβ and MS4A6A proteins points toward additional complex mechanisms for FcεRI trafficking and signaling

BackgroundAllergic diseases are triggered by signaling through the high-affinity IgE receptor, Fc epsilon RI. In both mast cells (MCs) and basophils, Fc epsilon RI is a tetrameric receptor complex comprising a ligand-binding alpha subunit (Fc epsilon RI alpha), a tetraspan beta subunit (Fc epsilon RI beta, MS4A2) responsible for trafficking and signal amplification, and a signal transducing dimer of single transmembrane gamma subunits (Fc epsilon RI gamma). However, Fc epsilon RI also exists as presumed trimeric complexes that lack Fc epsilon RI beta and are expressed on several cell types outside the MC and basophil lineages. Despite known differences between humans and mice in the presence of the trimeric Fc epsilon RI complex, questions remain as to how it traffics and whether it signals in the absence of Fc epsilon RI beta. We have previously reported that targeting Fc epsilon RI beta with exon-skipping oligonucleotides eliminates IgE-mediated degranulation in mouse MCs, but equivalent targeting in human MCs was not effective at reducing degranulation. ResultsHere, we report that the Fc epsilon RI beta-like protein MS4A6A exists in human MCs and compensates for Fc epsilon RI beta in Fc epsilon RI trafficking and signaling. Human MS4A6A promotes surface expression of Fc epsilon RI complexes and facilitates degranulation. MS4A6A and Fc epsilon RI beta are encoded by highly related genes within the MS4A gene family that cluster within the human gene loci 11q12-q13, a region linked to allergy and asthma susceptibility. ConclusionsOur data suggest the presence of either Fc epsilon RI beta or MS4A6A is sufficient for degranulation, indicating that MS4A6A could be an elusive Fc epsilon RI beta-like protein in human MCs that performs compensatory functions in allergic disease.

Automated summary

This study found that the Fc epsilon RI beta-like protein MS4A6A exists in human mast cells and can compensate for the role of Fc epsilon RI beta in trafficking and signaling.