Dedicator of cytokinesis protein 2 couples with lymphoid enhancer-binding factor 1 to regulate expression of CD21 and B-cell differentiation
Dedicator of cytokinesis protein 2 couples with lymphoid enhancer-binding factor 1 to regulate expression of CD21 and B-cell differentiation
复制标题
胞质分裂蛋白 2 的奉献者与淋巴增强子结合因子 1 结合调节 CD21 的表达和 B 细胞分化
DOI：
10.1016/j.jaci.2019.05.041
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发表时间：
2019-11-01
影响因子：
14.2
通讯作者：
Liu, Chaohong
中科院分区：
文献类型：
--
作者：
Jing, Yukai;Kang, Danqing;Liu, Chaohong
背景：B细胞受体（BCR）信号，结合CD 19和CD 21信号，赋予B细胞反应的特异性控制。胞质分裂贡献蛋白2（DOCK 2）对淋巴细胞的迁移和运动至关重要。虽然DOCK 2的缺失导致淋巴细胞减少，但是关于DOCK 2在B细胞中的信号传导机制和生理功能知之甚少。目的：我们试图确定DOCK 2如何调节BCR信号传导和外周B细胞分化的潜在分子机制。在这项研究中，我们使用了DOCK 2，Wiskott-Aldrich综合征蛋白（WASP），和淋巴增强子结合因子1缺乏，以研究它们在BCR信号传导和B细胞分化中的相互作用。我们发现，DOCK 2的缺失导致近端和远端BCR信号分子（包括CD 19）下调，但含SH 2的肌醇5磷酸酶1上调，一种负信号分子有趣的是，DOCK 2缺陷在mRNA和/或蛋白质水平上降低了CD 19和CD 21的表达，并且与边缘区B细胞数量的减少相关。此外，DOCK 2的缺失减少了WASP的活化并加速了WASP的降解，导致肌动蛋白积累减少和B细胞的早期活化。从机制上讲，DOCK 2的缺乏上调淋巴增强子结合因子1的表达。这些差异与DOCK 2缺失时体液免疫应答的改变有关。结论：DOCK 2缺失导致CD 19介导的BCR信号转导和边缘区B细胞分化下调，从而调节CD 21的表面表达，这可能是DOCK 2缺失导致边缘区B细胞分化下调的分子机制。
Background: B-cell receptor (BCR) signaling, combined with CD19 and CD21 signals, imparts specific control of B-cell responses. Dedicator of cytokinesis protein 2 (DOCK2) is critical for the migration and motility of lymphocytes. Although absence of DOCK2 leads to lymphopenia, little is known about the signaling mechanisms and physiologic functions of DOCK2 in B cells.Objective: We sought to determine the underlying molecular mechanism of how DOCK2 regulates BCR signaling and peripheral B-cell differentiation.Methods: In this study we used genetic models for DOCK2, Wiskott-Aldrich syndrome protein (WASP), and lymphoid enhancer-binding factor 1 deficiency to study their interplay in BCR signaling and B-cell differentiation.Results: We found that the absence of DOCK2 led to downregulation of proximal and distal BCR signaling molecules, including CD19, but upregulation of SH2-containing inositol 5 phosphatase 1, a negative signaling molecule. Interestingly, DOCK2 deficiency reduced CD19 and CD21 expression at the mRNA and/or protein levels and was associated with reduced numbers of marginal zone B cells. Additionally, loss of DOCK2 reduced activation of WASP and accelerated degradation of WASP, resulting into reduced actin accumulation and early activation of B cells. Mechanistically, the absence of DOCK2 upregulates the expression of lymphoid enhancer-binding factor 1. These differences were associated with altered humoral responses in the absence of DOCK2.Conclusions: Overall, our study has provided a novel underlying molecular mechanism of how DOCK2 deficiency regulates surface expression of CD21, which leads to downregulation of CD19-mediated BCR signaling and marginal zone B-cell differentiation.