LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation.
LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation.
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DOI：
10.1038/srep25738
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发表时间：
2016-05-11
影响因子：
4.6
通讯作者：
Kumanogoh A
中科院分区：
文献类型：
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作者：
Morimoto K;Baba Y;Shinohara H;Kang S;Nojima S;Kimura T;Ito D;Yoshida Y;Maeda Y;Sarashina-Kida H;Nishide M;Hosokawa T;Kato Y;Hayama Y;Kinehara Y;Okuno T;Takamatsu H;Hirano T;Shima Y;Narazaki M;Kurosaki T;Toyofuku T;Kumanogoh A
B细胞受体(BCR)信号在B细胞活化和体液免疫中起重要作用。在这项研究中，我们发现了富含亮氨酸的重复蛋白激酶1(LRRK1)在BCR介导的免疫反应中的关键作用。Lrrk1−/−小鼠表现出B1a细胞发育和基础免疫球蛋白产生的改变。此外，由于IgG3类开关重组的缺陷，这些小鼠无法产生针对T细胞非依赖性2型抗原的IgG3抗体。与此同时，缺乏LRRK1的B细胞在bcr刺激下表现出严重的增殖和存活缺陷，这与bcr介导的NF-κB活性降低和NF-κB靶基因Bclxl、Cyclin D2和NFATc1/αA的表达减少有关。此外，LRRK1与CARMA1物理上相互作用并有效地协同增强了NF-κB的激活。我们的结果揭示了LRRK1在B细胞中的NF-κB信号和体液免疫反应中的关键作用。
B-cell receptor (BCR) signaling plays a critical role in B-cell activation and humoral immunity. In this study, we discovered a critical function of leucine-rich repeat kinase 1 (LRRK1) in BCR-mediated immune responses. Lrrk1−/− mice exhibited altered B1a-cell development and basal immunoglobulin production. In addition, these mice failed to produce IgG3 antibody in response to T cell–independent type 2 antigen due to defects in IgG3 class-switch recombination. Concomitantly, B cells lacking LRRK1 exhibited a profound defect in proliferation and survival upon BCR stimulation, which correlated with impaired BCR-mediated NF-κB activation and reduced expression of NF-κB target genes including Bcl-xL, cyclin D2, and NFATc1/αA. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-κB activation. Our results reveal a critical role of LRRK1 in NF-κB signaling in B cells and the humoral immune response.
定义MU-> gamma3开关重组的同种特异性的功能重组基序的映射暗示NF-kappab P50是同种型特异性开关因子。
DOI：
10.1084/jem.20031935
发表时间：
2004-03-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Kenter AL;Wuerffel R;Dominguez C;Shanmugam A;Zhang H
通讯作者：
Zhang H