B- and T-cell development both involve activity of the unfolded protein response pathway
B- and T-cell development both involve activity of the unfolded protein response pathway
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DOI：
10.1074/jbc.m801395200
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发表时间：
2008-06-27
影响因子：
4.8
通讯作者：
Niwa, Maho
中科院分区：
文献类型：
--
作者：
Brunsing, Ryan;Omori, Sidne A.;Niwa, Maho
未折叠蛋白反应（UPR）信号通路调节内质网蛋白折叠的功能能力。除了UPR信号在成熟B细胞终末分化为分泌抗体的浆细胞过程中的作用之外，UPR信号在造血过程中的状态或重要性尚未被探索，部分原因是难以分离足够量的处于发育中间阶段的细胞以进行生化分析。在用携带荧光UPR报告构建体的造血细胞重建辐射小鼠后，我们发现IRE 1剪接XBP 1的核酸酶活性在T和B淋巴细胞分化的早期阶段是活跃的：在骨髓pro-B细胞和CD 4（+）CD 8（+）双阳性胸腺T细胞中。IRE 1在晚期B细胞中无活性。在T细胞中，在更成熟的CD 4（+）T细胞群体中未检测到IRE活性，但在CD 8（+）细胞毒性T细胞群体中具有活性。在淋巴细胞分化过程中，多种信号可能参与激活IRE 1，包括抗原受体基因重排。我们的研究结果表明，转基因造血干细胞提供了一个快速和简单的手段，以确定在生理环境中的UPR信号成分激活。
The unfolded protein response (UPR) signaling pathway regulates the functional capacity of the endoplasmic reticulum for protein folding. Beyond a role for UPR signaling during terminal differentiation of mature B cells to antibody-secreting plasma cells, the status or importance of UPR signaling during hematopoiesis has not been explored, due in part to difficulties in isolating sufficient quantities of cells at developmentally intermediate stages required for biochemical analysis. Following reconstitution of irradiated mice with hematopoietic cells carrying a fluorescent UPR reporter construct, we found that IRE1 nuclease activity for XBP1 splicing is active at early stages of T-and B-lymphocyte differentiation: in bone marrow pro-B cells and in CD4(+)CD8(+) double positive thymic T cells. IRE1 was not active in B cells at later stages. In T cells, IRE activity was not detected in the more mature CD4(+) T-cell population but was active in the CD8(+) cytotoxic T-cell population. Multiple signals are likely to be involved in activating IRE1 during lymphocyte differentiation, including rearrangement of antigen receptor genes. Our results show that reporter-transduced hematopoietic stem cells provide a quick and easy means to identify UPR signaling component activation in physiological settings.