Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1
Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1
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DOI：
10.1074/jbc.m705262200
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发表时间：
2008-01-11
影响因子：
4.8
通讯作者：
Garrett-Sinha, Lee Ann
中科院分区：
文献类型：
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作者：
John, Shinu A.;Clements, James L.;Garrett-Sinha, Lee Ann
从B细胞发育出分泌免疫球蛋白的浆细胞是一个严格调控的过程，受许多转录因子的作用控制。特别是，转录因子Blimp-1通过抑制成熟B细胞程序中涉及的基因的表达，是浆细胞分化的关键正向调节因子。转录因子Ets-1是浆细胞分化的负调控因子，在Ets-1基因敲除小鼠中，分泌IgM的浆细胞数量增加表明这一点。我们之前已经证明，ETS-1缺陷的B细胞在Toll样受体9(TLR9)信号的作用下，会增强分化为分泌IgM的浆细胞。我们现在探索ETS-1限制TLR9下游分化的机制。我们的结果表明，Ets-1与Blimp-1在物理上相互作用，这导致Blimp-1的DNA结合活性被阻断，Blimp-1在不干扰Blimp-1蛋白水平的情况下抑制靶基因的能力降低。此外，我们还发现Ets-1诱导了几个被Blimp-1抑制的靶基因的表达，包括Pax-5。这些结果揭示了ETS-1控制Blimp-1活性的未知机制，并提示在发生浆细胞分化之前，必须下调Ets-1的表达。
Development of immunoglobulin-secreting plasma cells from B cells is a tightly regulated process controlled by the action of a number of transcription factors. In particular, the transcription factor Blimp-1 is a key positive regulator of plasmacytic differentiation via its ability to suppress expression of genes involved in the mature B cell program. The transcription factor Ets-1 is a negative regulator of plasmacytic differentiation, as indicated by the development of increased numbers of IgM-secreting plasma cells in Ets-1 knock-out mice. We have previously shown that Ets-1-deficient B cells undergo enhanced differentiation into IgM-secreting plasma cells in response to Toll-like receptor 9 (TLR9) signaling. We now explore the mechanism by which Ets-1 limits differentiation downstream of TLR9. Our results indicate that Ets-1 physically interacts with Blimp-1, which leads to a block in Blimp-1 DNA binding activity and a reduction in the ability of Blimp-1 to repress target genes without interfering with Blimp-1 protein levels. In addition, we show that Ets-1 induces the expression of several target genes that are repressed by Blimp-1, including Pax-5. These results reveal a previously unknown mechanism for the control of Blimp-1 activity by Ets-1 and suggest that expression of Ets-1 must be down-regulated before plasmacytic differentiation can occur.