Identification of redundancy between human FcɛRIβ and MS4A6A proteins points toward additional mechanisms for FcɛRI trafficking and signaling

Abstract Allergic diseases are triggered by signaling through the high affinity IgE receptor, FcɛRI. In mast cells (MCs) and basophils, FcɛRI is a tetrameric receptor complex comprising a ligand binding α subunit (FcɛRIα); a tetraspan β subunit (FcɛRIβ) responsible for trafficking the complex and amplifying signaling; and a signal transducing dimer of single transmembrane γ subunits (FcɛRIγ). However, FcɛRI also exist as presumed trimeric complexes that lack FcɛRIβ and are expressed on several cell types outside of the MC and basophil compartments. There are known differences in the trimeric FcɛRI complex between humans and mice and questions remain as to how this trimeric FcɛRI complex traffics and whether it signals in the absence of FcɛRIβ. We have previously reported that targeting FcɛRIβ with exon skipping oligonucleotides diminishes IgE-mediated degranulation in mouse MCs, but equivalent targeting in human MCs was not effective at reducing degranulation. Here, we report that an FcɛRIβ-like protein exists in humans and we identify that the Membrane Spanning 4A (MS4A) gene cluster member, MS4A6A compensates for FcɛRIβ in FcɛRI trafficking and signaling. The function of MS4A6A is currently unknown, but MS4A6A and FcɛRIβ are encoded by highly related genes within the same family (MS4A gene family) that cluster within the human gene loci 11q12–q13, a region linked to allergy and asthma susceptibility. Human MS4A6A promotes surface expression of FcɛRI complexes and promotes degranulation. Indeed, our data suggest the presence of either FcɛRIβ or MS4A6A is sufficient for degranulation. This study suggests that MS4A6A could be an elusive FcɛRIβ-like protein in human MCs that performs compensatory functions to FcɛRIβ. Research was supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Award Number R01AI143985, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, start-up funds, Institutional National Research Service Award from the Office of the Director of National Institutes of Health, NIH T32OD011130.