酪氨酸蛋白激酶Btk在B細(xì)胞受體信號(hào)傳導(dǎo)中起重要作用。Btk基因突變導(dǎo)致人與小鼠發(fā)生免疫缺陷。該項(xiàng)研究揭示了Btk轉(zhuǎn)錄調(diào)節(jié)的新機(jī)制—組蛋白乙酰轉(zhuǎn)移酶p300介導(dǎo)的組蛋白乙酰化正調(diào)，而組蛋白去乙酰化酶1介導(dǎo)的組蛋白去乙酰化負(fù)調(diào)Btk轉(zhuǎn)錄及表達(dá)。同時(shí)，該研究發(fā)現(xiàn)Btk蛋白可以發(fā)生乙酰化修飾，Btk蛋白的乙酰化可通過(guò)蛋白激酶Lyn影響B(tài)tk蛋白磷酸化。這些結(jié)果拓展了對(duì)Btk調(diào)節(jié)及其功能的認(rèn)識(shí)，并有益于對(duì)相關(guān)疾病的研究。

蛋白乙酰化由乙酰轉(zhuǎn)移酶和去乙酰化酶動(dòng)態(tài)調(diào)節(jié)。進(jìn)一步的研究發(fā)現(xiàn)體內(nèi)與體外B細(xì)胞激活有意義的誘導(dǎo)細(xì)胞內(nèi)乙酰轉(zhuǎn)移酶活性增加，但是去乙酰化酶活性并不降低，這一結(jié)果揭示了B細(xì)胞激活誘導(dǎo)的（組蛋白和非組蛋白）乙酰化是如何調(diào)節(jié)的。這一結(jié)果亦有助于研究其他免疫細(xì)胞（如T細(xì)胞）激活的乙酰化調(diào)節(jié)。

此外，這項(xiàng)研究還報(bào)道了組蛋白去乙酰化酶抑制劑TSA誘導(dǎo)Btk mRNA降解。有趣的是，TSA的這一作用并非通過(guò)抑制組蛋白去乙酰化酶活性。TSA被廣泛地應(yīng)用于基礎(chǔ)及臨床研究。已知TSA可導(dǎo)致許多（2-10%）基因的mRNA水平降低，但通常認(rèn)為TSA是通過(guò)對(duì)組蛋白去乙酰化酶活性的抑制起作用的。

Lysine Acetylation Regulates Bruton's Tyrosine Kinase in B Cell Activation

Zhijian Liu,* Antonello Mai, and Jian Sun*

*Laboratory of B-Cell and Autoantibody, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, and ?Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai JiaoTong University School of Medicine, Shanghai; Institute of Genetics and Developmental Biology, and Graduate School, Chinese Academy of Sciences, Beijing, China; and Dipartimento di Studi Farmaceutici, Universita degli Studi di Roma La Sapienza, Rome, Italy

Bruton's tyrosine kinase （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 show that BCR cross-linking induces histone lysine acetylation at the Btk promoter, correlating with marked recruitment of histone acetyltransferase E1A-associated 300-kDa protein （p300） to the locus. These effects enhance Btk promoter activity and increase the expression of Btk mRNA and protein. Consistent with these results, activated B cells display increased p300 expression and total histone acetyltransferase activity in vitro and in vivo, resulting in global histone acetylation. Interestingly, we found that BCR signaling induces Btk lysine acetylation mediated by p300. Moreover, lysine acetylation of Btk promotes its phosphorylation. Together, our results indicate a novel regulatory mechanism for Btk transcription and reveal a previously unrecognized posttranslational modification of the Btk protein and its association with phosphorylation in B cell activation.