A truncated splice-variant of the FcεRIβ receptor subunit is critical for microtubule formation and degranulation in mast cells.
A truncated splice-variant of the FcεRIβ receptor subunit is critical for microtubule formation and degranulation in mast cells.
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DOI：
10.1016/j.immuni.2013.04.007
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发表时间：
2013-05-23
期刊：
影响因子：
32.4
通讯作者：
Metcalfe DD
中科院分区：
文献类型：
--
作者：
Cruse G;Beaven MA;Ashmole I;Bradding P;Gilfillan AM;Metcalfe DD
人类连锁分析表明，含有MS 4A 2的基因座（编码FcεRIβ）是过敏易感性的候选基因。我们已经在人体中鉴定了FcεRIβ（t-FcεRIβ）的截短体，其含有推定的钙调蛋白结合结构域，因此，我们试图鉴定该变体在肥大细胞功能中的作用。我们确定t-FcεRIβ对微管形成和脱粒至关重要，并且它可能通过响应Ca 2+信号将衔接子分子和激酶运输到核粒体周围和高尔基体区域来执行此功能。突变研究表明，在Ca 2+存在下，钙调素与t-FcεRIβ的结合可能对t-Fc ε RIβ的功能至关重要。此外，t-FcεRIβ的基因靶向减弱了微管形成、脱粒和Ca 2+信号下游的IL-8产生。因此，t-FcεRIβ介导Ca 2+依赖性微管形成，从而促进脱粒和细胞因子释放。由于t-FcεRIβ具有这种关键功能，因此它代表了下调过敏性炎症的治疗靶点。
Human linkage analyses have implicated the MS4A2-containing gene locus (encoding FcεRIβ) as a candidate for allergy susceptibility. We have identified a truncation of FcεRIβ (t-FcεRIβ) in humans which contains a putative calmodulin binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-FcεRIβ is critical for microtubule formation and degranulation and that it may perform this function by trafficking adapter molecules and kinases to the pericentrosomal and Golgi region in response to Ca2+ signals. Mutagenesis studies suggest that calmodulin binding to t-FcεRIβ in the presence of Ca2+ could be critical for t-FcεRIβ function. In addition, gene targeting of t-FcεRIβ attenuated microtubule formation, degranulation and IL-8 production downstream of Ca2+ signals. Therefore, t-FcεRIβ mediates Ca2+-dependent microtubule formation, which promotes degranulation and cytokine release. Because t-FcεRIβ has this critical function, it represents a therapeutic target for the down-regulation of allergic inflammation.
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