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 FcεRIβ (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 FcεRIβ, has related functions to FcεRIβ in FcεRI signaling. We establish in this study that MS4A4A promotes phosphorylation of PLCγ1, calcium flux and degranulation in response to IgE-mediated crosslinking of FcεRI. We previously demonstrated that MS4A4A promotes recruitment of KIT into caveolin-1-enriched microdomains and signaling through PLCγ1. 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 FcεRI and KIT into lipid rafts. In addition to proximal FcεRI 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 FcεRI 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 FcεRIβ to promote PLCγ1 signaling, SOCE, and degranulation through FcεRI in human mast cells and thus represents a new target in the regulation of IgE-mediated mast cell activation.

中文翻译：

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FcεRIβ 同源物 MS4A4A 可促进 FcεRI 信号转导和储存操作的 Ca2+ 在人肥大细胞中的进入。

跨膜 4A (MS4A) 基因家族的成员聚集在 11q12-13 附近，该区域与过敏和哮喘易感性有关。除了 FcεRIβ (MS4A2) 和 CD20 (MS4A1) 在肥大细胞和 B 细胞信号传导中的已知功能外，其余 MS4A 蛋白的功能研究尚缺乏。因此，我们探讨了 MS4A4A（一种表达 FcεRIβ 同源物的肥大细胞）是否在 FcεRI 信号传导中与 FcεRIβ 具有相关功能。我们在这项研究中确定，MS4A4A 响应 IgE 介导的 FcεRI 交联，促进 PLCγ1 的磷酸化、钙通量和脱粒。我们之前已经证明 MS4A4A 促进 KIT 募集到富含 caveolin-1 的微区并通过 PLCγ1 发出信号。Caveolin-1 本身是 IgE 依赖的钙池操纵 Ca2+ 进入 (SOCE) 的重要调节因子，并促进钙池操纵的 Ca2+ 通道成孔单元 Orai1 的表达。因此，我们进一步报告说，MS4A4A 通过与caveolin-1 的相互作用以及将 FcεRI 和 KIT 募集到脂筏中而发挥作用。除了近端 FcεRI 信号，我们同样表明 MS4A4A 调节 Orai1 介导的钙进入下游钙从钙库释放。MS4A4A 和 Orai1 对化合物 48/80 刺激的影响有限，表明这两种蛋白质对 FcεRI 受体信号传导的选择性高于 Mas 相关 G 蛋白偶联受体 X2 信号传导。总体而言，我们的数据与 MS4A4A 对同源 FcεRIβ 执行相关功能以促进 PLCγ1 信号传导、SOCE、