GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT6-signaling to IgE production in B cells
GANP suppresses the arginine methyltransferase PRMT5 regulating IL-4-mediated STAT6-signaling to IgE production in B cells
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DOI：
10.1016/j.molimm.2008.08.272
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发表时间：
2009-03-01
影响因子：
3.6
通讯作者：
Sakaguchi, Nobuo
中科院分区：
文献类型：
--
作者：
Igarashi, Hideya;Kuwahara, Kazuhiko;Sakaguchi, Nobuo
抗原（Ag）驱动的B细胞在生发中心（GC）B细胞中经历抗体（Ab）亲和力成熟和类别转换。GANP是Ab亲和力成熟所需的分子之一。我们在此发现了B细胞GANP缺陷小鼠中IgE的增加，并研究了GANP调节的信号转导途径。GANP通过与JAK结合蛋白精氨酸甲基转移酶（PRMT）5和JAK 1/JAK 3相互作用调节精氨酸甲基转移酶活性，从而抑制STAT介导的GC B细胞转录活性。在体外和体内刺激后，胃癌B细胞中的B细胞prmt 5 mRNA表达上调。体外实验发现，LIPS和IL-4刺激后，GANP的缺失导致B细胞中STAT 6的磷酸化和精氨酸二甲基化水平上调。相反，在ganp基因转基因小鼠中，GANP过表达的B细胞在刺激后显示出低的STAT 6磷酸化。荧光素酶报告基因检测结果显示，PRMT 5的过表达可上调STAT 6介导的基因转录，而GANP的共转染可抑制STAT 6介导的基因转录。GANP通过调节精氨酸甲基化活性下调JAK 1/JAK 3向STAT 6的信号转导，这可能是高IgE对B细胞内源性抑制机制的重要机制。(C)2008爱思唯尔有限公司保留所有权利。
Antigen (Ag)-driven B cells undergo antibody (Ab) affinity maturation and class switching in germinal center (GC) B cells. GANP is one of the molecules required for Ab affinity maturation. We herein found an increase of IgE in B cell ganp-deficient mice and studied the signal transduction pathway regulated by GANP. GANP suppresses the STAT-mediated transcription activity in GC B cells with the regulation of arginine methyltransferase activity by the interaction with JAK-binding protein arginine methyltransferase (PRMT) 5 and JAK1/JAK3 that are responsible for STAT6 activation. The prmt5 mRNA was up-regulated in B cells after stimulation in vitro and in vivo in GC B cells. The loss of GANP caused up-regulation of phosphorylation and arginine dimethylation of STAT6 in B cells after stimulation with LIPS and IL-4 in vitro. On the contrary, GANP over-expressed B cells in ganp gene-transgenic mice showed a low STAT6 phosphorylation after stimulation. The over-expression of PRMT5 caused the up-regulation of STAT6-mediated gene transcription, which was also suppressed by the co-transfection of GANP, in luciferase reporter assay. GANP down-regulates JAK1/JAK3 to STAT6-signaling with regulation of arginine methylation activity, which might be responsible for the B cell endogenous suppressive mechanism of hyper-IgE. (C) 2008 Elsevier Ltd. All rights reserved.