WASP and Mst1 coregulate B-cell development and B-cell receptor signaling
WASP and Mst1 coregulate B-cell development and B-cell receptor signaling
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WASP 和 Mst1 共同调节 B 细胞发育和 B 细胞受体信号传导
DOI：
10.1182/bloodadvances.2018027870
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发表时间：
2020-02-11
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：
Huang, Lu;Sun, Xiaoyu;Liu, Chaohong
mst 1是一种丝氨酸/苏氨酸激酶，参与细胞存活、增殖、凋亡和肿瘤发生。在小鼠中，Mst 1调节T细胞粘附和迁移所需的肌动蛋白动力学，这与胸腺进出淋巴组织相关。Mst 1在B细胞中的作用以及它如何控制肌动蛋白依赖性过程尚未得到很好的表征。Wiskott-Aldrich综合征蛋白（WASP）缺乏仅中度影响发育和B细胞受体（BCR）信号传导，但WASP可能与其他分子相关。我们研究了Mst 1是否与WASP相关，以调节B细胞的发育和激活。在Mst 1/WASP双敲除（DKO）小鼠的实验中，我们发现骨髓B细胞发育严重缺陷，DKO小鼠中的BCR信号严重减少。尽管WASP或Mst 1可以影响早期B细胞活化，但我们发现DKO小鼠的B细胞中的早期活化事件，如B细胞扩散、BCR聚集和BCR信号传导受到更大的损害。此外，在WASP和Mst 1 KO小鼠中观察到Mst 1和WASP之间的相互调节，从而在Mst 1 KO小鼠中影响磷酸化WASP的定位和功能。最重要的是，Mst 1通过降低WASP相互作用蛋白的表达来抑制WASP的表达。有趣的是，我们还发现患者和小鼠中的WASP缺乏会干扰磷酸化的Mst 1定位，从而干扰B细胞中的功能。总之，我们的研究为WASP调节B细胞发育和BCR信号传导提供了一个合作伙伴，以及相互调节的分子机制。
Mst1 is a serine/ threonine kinase involved in cell survival, proliferation, apoptosis, and tumorigenesis. In mice, Mst1 regulates actin dynamics required for T-cell adhesion and migration, which correlate with thymic egress and entry into lymphatic tissue. The role of Mst1 in B cells and how it may control actin-dependent processes has not been well characterized. Wiskott-Aldrich syndrome protein (WASP) deficiency only moderately affects development and B-cell receptor (BCR) signaling, suggestingWASP likely associates with other molecules. We investigated whether Mst1 associates with WASP to regulate B-cell development and activation. Experimenting on Mst1/WASP double knockout (DKO) mice, we found a severe defect in the bone marrow B-cell development, and BCR signaling in the DKO mice was severely reduced. Even though WASP or Mst1 could influence the early B-cell activation, we found that the early activation events such as B-cell spreading, BCR clustering, and BCR signaling weremuchmore impaired in the B cells from DKOmice. Furthermore, reciprocal regulation between Mst1 and WASP was observed in WASP and Mst1 KO mice, whereby the localization and function of phosphorylated WASP were affected in Mst1 KO mice. Most importantly, Mst1 inhibits the expression of WASP by decreasing the expression of WASP-interacting protein. Interestingly, we also found that WASP deficiency in patients and mice interferes with phosphorylated Mst1 localization and therefore function in B cells. Overall, our study provides a partner for WASP to regulate B-cell development and BCR signaling, as well as the reciprocal regulating molecular mechanism of one another.