XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells.
XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells.
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DOI：
10.1038/emboj.2009.117
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发表时间：
2009-06-03
期刊：
影响因子：
11.4
通讯作者：
Ploegh, Hidde L.
中科院分区：
文献类型：
--
作者：
Hu, Chih-Chi Andrew;Dougan, Stephanie K.;McGehee, Annette M.;Love, J. Christopher;Ploegh, Hidde L.
XBP-1是一种驱动未折叠蛋白反应（UPR）的转录因子，在B细胞分化为浆细胞时被激活。在这里，我们发现在分泌IgM的能力被消除的B细胞中，XBP-1在诱导分化时正常被诱导，这表明B细胞中XBP-1的激活是一个依赖于分化的事件，而不是由分泌IgM的大量合成引起的UPR的结果。没有XBP-1， B细胞不能通过B细胞受体有效地发出信号。信号缺陷导致浆细胞转录因子IRF4和Blimp-1表达异常，激活诱导胞苷脱氨酶和鞘氨醇-1-磷酸受体水平改变。使用xbp -1缺陷/Blimp-1-GFP转基因小鼠，我们发现xbp -1缺陷的B细胞在初始免疫反应中形成分泌抗体的质母细胞；然而，这些浆母细胞对CXCL12反应无效。它们不能在骨髓中定植，也不能维持抗体的产生。这些发现确定了XBP-1在正常浆细胞发育中的作用，并对b细胞恶性肿瘤的治疗具有指导意义。
XBP-1, a transcription factor that drives the unfolded protein response (UPR), is activated in B cells when they differentiate to plasma cells. Here, we show that in the B cells, whose capacity to secrete IgM has been eliminated, XBP-1 is induced normally on induction of differentiation, suggesting that activation of XBP-1 in B cells is a differentiation-dependent event, but not the result of a UPR caused by the abundant synthesis of secreted IgM. Without XBP-1, B cells fail to signal effectively through the B-cell receptor. The signalling defects lead to aberrant expression of the plasma cell transcription factors IRF4 and Blimp-1, and altered levels of activation-induced cytidine deaminase and sphingosine-1-phosphate receptor. Using XBP-1-deficient/Blimp-1-GFP transgenic mice, we find that XBP-1-deficient B cells form antibody-secreting plasmablasts in response to initial immunization; however, these plasmablasts respond ineffectively to CXCL12. They fail to colonize the bone marrow and do not sustain antibody production. These findings define the role of XBP-1 in normal plasma cell development and have implications for management of B-cell malignancies.
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