Xing Yan, Igarashi Hideya, Wang Xiaodan, Sakaguchi Nobuo
Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Japan.
J Exp Med. 2005 Sep 5;202(5):707-19. doi: 10.1084/jem.20050637. Epub 2005 Aug 29.
B cell receptor (BCR) cross-linking induces B cell proliferation and sustains survival through the phosphorylation-dependent signals. We report that a loss of the protein phosphatase component G5PR increased the activation-induced cell death (AICD) and thus impaired B cell survival. G5PR associates with GANP, whose expression is up-regulated in mature B cells of the peripheral lymphoid organs. To study G5PR function, the G5pr gene was conditionally targeted with the CD19-Cre combination (G5pr(-/-) mice). The G5pr(-/-) mice had a decreased number of splenic B cells (60% of the controls). G5pr(-/-) B cells showed a normal proliferative response to lipopolysaccharide or anti-CD40 antibody stimulation but not to BCR cross-linking with or without IL-4 in vitro. G5pr(-/-) B cells did not show abnormalities in the BCR-mediated activation of Erks and NF-kappaB, cyclin D2 induction, or Akt activation. However, G5pr(-/-) B cells were sensitive to AICD caused by BCR cross-linking. This was associated with an increased depolarization of the mitochondrial membrane and the enhanced activation of c-Jun NH(2)-terminal protein kinase and Bim. These results suggest that G5PR is required for the BCR-mediated proliferation associated with the prevention of AICD in mature B cells.
B细胞受体（BCR）交联通过磷酸化依赖性信号诱导B细胞增殖并维持其存活。我们报告称，蛋白磷酸酶成分G5PR的缺失增加了活化诱导的细胞死亡（AICD），从而损害了B细胞的存活。G5PR与GANP相关联，GANP在外周淋巴器官成熟B细胞中的表达上调。为了研究G5PR的功能，利用CD19-Cre组合有条件地靶向G5pr基因（G5pr基因敲除小鼠）。G5pr基因敲除小鼠的脾脏B细胞数量减少（为对照组的60%）。G5pr基因敲除的B细胞对脂多糖或抗CD40抗体刺激表现出正常的增殖反应，但在体外对有或无IL-4的BCR交联无反应。G5pr基因敲除的B细胞在BCR介导的Erks和NF-κB激活、细胞周期蛋白D2诱导或Akt激活方面未表现出异常。然而，G5pr基因敲除的B细胞对BCR交联引起的AICD敏感。这与线粒体膜去极化增加以及c-Jun NH(2)-末端蛋白激酶和Bim的激活增强有关。这些结果表明，G5PR是成熟B细胞中与预防AICD相关的BCR介导增殖所必需的。
