The FcεRIβ homologue, MS4A4A, promotes FcεRI signal transduction and store-operated Ca2+ entry in human mast cells

Members of the membrane spanning 4A (MS4A) gene family are clustered around 11q12-13, a region linked to allergy and asthma susceptibility. Other than the known functions of Fc epsilon RI beta (MS4A2) and CD20 (MS4A1) in mast cell and B cell signaling, respectively, functional studies for the remaining MS4A proteins are lacking. We thus explored whether MS4A4A, a mast cell expressed homologue of Fc epsilon RI beta, has related functions to Fc epsilon RI beta in Fc epsilon RI signaling. We establish in this study that MS4A4A promotes phosphorylation of PLC gamma 1, calcium flux and degranulation in response to IgE-mediated crosslinking of Fc epsilon RI. We previously demonstrated that MS4A4A promotes recruitment of KIT into caveolin-1-enriched microdomains and signaling through PLC gamma 1. Caveolin-1 itself is an important regulator of IgE-dependent store-operated Ca2+ entry (SOCE) and promotes expression of the store-operated Ca2+ channel pore-forming unit, Orai1. We thus further report that MS4A4A functions through interaction with caveolin-1 and recruitment of Fc epsilon RI and KIT into lipid rafts. In addition to proximal Fc epsilon RI signaling, we similarly show that MS4A4A regulates Orai1-mediated calcium entry downstream of calcium release from stores. Both MS4A4A and Orai1 had limited effects with compound 48/80 stimulation, demonstrating some degree of selectivity of both proteins to Fc epsilon RI receptor signaling over Mas-related G Protein coupled receptor X2 signaling. Overall, our data are consistent with the conclusion that MS4A4A performs a related function to the homologous Fc epsilon RI beta to promote PLC gamma 1 signaling, SOCE, and degranulation through Fc epsilon RI in human mast cells and thus represents a new target in the regulation of IgE-mediated mast cell activation.