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首页> 外文期刊>Cellular Signalling >The Fc epsilon RI beta homologue, MS4A4A, promotes Fc epsilon RI signal transduction and store-operated Ca2+ entry in human mast cells
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The Fc epsilon RI beta homologue, MS4A4A, promotes Fc epsilon RI signal transduction and store-operated Ca2+ entry in human mast cells

机译:Fcε5Rβ同源物MS4a4a,促进人肥大细胞中的Fcεri信号转导和存储操作的Ca2 +进入

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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.
机译:跨越4A(MS4A)基因家族的膜的成员在11Q12-13左右聚集,是与过敏和哮喘易感性相关的区域。除了Fcε5β(MS4A2)和CD20(MS4A1)中的已知功能,分别缺乏用于剩余MS4A蛋白的功能性研究。因此,我们探讨了MS4A4A是否表达了FCεRIβ的同源物,对FCεRI信号传导中的FC epsilonRIβ具有相关的功能。我们在本研究中建立了MS4A4A促进PLCγ1,钙通量和止血的磷酸化,响应于IgE介导的Fc Epsilon Ri的交联。我们之前证明MS4A4A促进试剂盒进入Caveolin-1富集的微摩粉,并通过PLCγ11。Caveolin-1本身是IgE依赖性储存的CA2 +进入(SOCE)的重要调节因子,并促进商店的表达 - 操作CA2 +通道成型单元,ORAI1。因此,我们进一步报告了MS4A4A通过与Caveolin-1的相互作用和募集FCε11和试剂盒中的脂质筏。除了近端FCεRI信号传导之外,我们还认为MS4A4A调节从商店的钙释放下游的ORAI1介导的钙入口。 MS4A4A和ORAI1都与化合物48/80刺激有有限的影响,证明了蛋白质的一定程度的选择性与MAS相关的G蛋白偶联受体X2信号传导。总的来说,我们的数据是一致的结论,即MS4A4A对同源FCεIIβ进行相关功能以促进PLCγ1信号传导,SOCE和通过人体肥大菌属中的FC epsilonRI进行脱粒,因此代表了该调节中的新目标IgE介导的肥大细胞活化。

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