酪氨酸蛋白激酶Btk表达与激活的组蛋白乙酰化调节

项目名称： 酪氨酸蛋白激酶Btk表达与激活的组蛋白乙酰化调节

项目编号： No.30872314

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 孙健

作者单位： 上海交通大学

项目金额： 30万元

中文摘要： Btk在B细胞受体信号传导中起关键作用。 Btk基因突变导致人与小鼠发生严重免疫缺陷病。我们首次报道了乙酰化对Btk的调节：1）揭示了Btk转录调节的新机制—#20057;酰转移酶p300介导的组蛋白乙酰化正调，而组蛋白去乙酰化酶1(HDAC1)介导的组蛋白去乙酰化负调Btk转录及表达;2）发现Btk蛋白可以发生乙酰化修饰, 并且Btk蛋白的乙酰化可通过蛋白激酶Lyn影响Btk蛋白的磷酸化。 这些结果拓展了对Btk调节及其功能的认识, 并有益于对相关疾病的研究;3）体内与体外B细胞激活有意义的诱导细胞内乙酰转移酶活性增加，但是去乙酰化酶活性并不降低，这一结果揭示了B细胞激活诱导的（组蛋白和非组蛋白）乙酰化在整体（global）水平是如何调节的。这一结果亦有助于研究其他(免疫)细胞（如T细胞）激活的乙酰化调节;(4) 我们还发现组蛋白去乙酰化酶抑制剂TSA诱导Btk mRNA降解。有趣的是，TSA的这一作用并非通过抑制组蛋白去乙酰化酶活性。TSA被广泛地应用于基础及临床研究。已知TSA可导致许多(2-10%)基因的mRNA水平降低，但通常认为TSA是通过对组蛋白去乙酰化酶活性的抑制起作用的。

中文关键词： 酪氨酸蛋白激酶Btk;B细胞受体信号;乙酰化;转录;磷酸化

英文摘要： Bruton’ tyrosine kinase (Btk) is a member of the nonreceptor tyrosine kinase Tec family. It is well known that Btk is involved in multiple signaling pathways following the activation of diverse cell membrane receptors. The role of Btk in BCR activation, however, has been the most studied, and results indicate that Btk is essential for BCR signal transduction and has diverse functions in B cells. Although Btk has been extensively studied, the role of lysine acetylation in Btk regulation has not been reported. In this study, we asked whether histone acetylation regulates Btk transcription, contributing to BCR-induced B cell activation. Our results demonstrate that the regulation of histone acetylation modulates Btk transcription and expression. In short, p300 promoted, whereas HDAC-1, -2, and -3 inhibited, the transcription and expression of Btk. Moreover, BCR signaling markedly recruited p300 to the Btk promoter and induced local histone acetylation. BCR-induced local acetylation, however, was not associated with reduced recruitment of HDAC-1 to the Btk locus. Consistent with these results, B cell activation in vitro with anti-μr LPS and in vivo by OVA led to global histone acetylation, which was coordinated with an increase in p300 expression and total HAT activity, but was not a result of reduced HDAC-1 expression or reduced activity of total HDACs. These results indicate that histone acetylation regulates Btk transcription. Furthermore, we found that BCR signaling induces Btk lysine acetylation mediated by p300 through interaction with Btk and that Btk acetylation promotes its phosphorylation via Lyn signaling. These results identify a novel posttranslational modification of the Btk protein and an association between Btk acetylation and phosphorylation. Together, our study links lysine acetylation with Btk regulation and sheds new light on B cell activation.

英文关键词： Bruton’ tyrosine kinase (Btk);BCR signaling;Acetylation;Transcription;Phosphorylation