Mst1 positively regulates B-cell receptor signaling via CD19 transcriptional levels
Mst1 positively regulates B-cell receptor signaling via CD19 transcriptional levels
复制标题
Mst1 通过 CD19 转录水平正向调节 B 细胞受体信号传导。
DOI：
10.1182/bloodadvances.2016000588
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发表时间：
2016-12-27
期刊：
影响因子：
7.5
通讯作者：
Liu, Chaohong
中科院分区：
文献类型：
--
作者：
Bai, Xiaoming;Huang, Lu;Liu, Chaohong
Mst激酶作为河马信号通路的关键调节因子，正在成为影响细胞增殖、器官大小、细胞迁移和细胞极性的关键信号分子之一。在B淋巴细胞中，Mst 1缺陷导致边缘区（MZ）B细胞的发育缺陷，但Mst 1如何调节B细胞受体（BCR）的活化和分化仍然是一个谜。使用基因操作的小鼠模型和全内反射荧光显微镜，我们已经证明Mst 1通过调节CD 19转录水平来正向调节BCR信号传导。与此一致，Mst 1缺陷小鼠表现出BCR信号传导减少，这与BCR聚集缺陷和B细胞在刺激性脂质双层上的扩散同时发生。Mst 1缺陷导致CD 19介导的Btk信号转导的破坏导致MZ和生殖中心B细胞分化的严重缺陷。机制分析表明，Mst 1通过调节转录因子TEAD 2上调CD 19的信使RNA水平，TEAD 2直接结合CD 19的3'非翻译区的共有基序。总之，我们的研究结果揭示了Mst 1在B细胞中的新功能以及Mst 1调节外周B细胞活化和分化的机制。
As a key regulator of hippo signaling pathway, Mst kinases are emerging as one of the key signaling molecules that influence cell proliferation, organ size, cell migration, and cell polarity. In B lymphocytes, Mst1 deficiency causes the developmental defect of marginal zone (MZ) B cells, but how Mst1 regulates B-cell receptor (BCR) activation and differentiation remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we have demonstrated that Mst1 positively regulates BCR signaling via modulating CD19 transcriptional levels. Consistent with this, Mst1-deficient mice exhibited reduced BCR signaling, which is concurrent with defective BCR clustering and B-cell spreading on stimulatory lipid bilayers. The disruption of CD19-mediated Btk signaling by Mst1 deficiency leads to the severe defect in the differentiation of MZ and germinal center B cells. Mechanistic analysis showed that Mst1 upregulates the messenger RNA level of CD19 via regulating the transcriptional factor TEAD2 that directly binds to the consensus motif in the 3' untranslated region of cd19. Overall, our results reveal a new function of Mst1 in B cells and the mechanism by which Mst1 regulates the activation and differentiation of peripheral B cells.