CUL7 E3 Ubiquitin Ligase Mediates the Degradation of Activation-Induced Cytidine Deaminase and Regulates the Ig Class Switch Recombination in B Lymphocytes
CUL7 E3 Ubiquitin Ligase Mediates the Degradation of Activation-Induced Cytidine Deaminase and Regulates the Ig Class Switch Recombination in B Lymphocytes
复制标题
CUL7 E3 泛素连接酶介导激活诱导的胞苷脱氨酶的降解并调节 B 淋巴细胞中的 Ig 类别转换重组
DOI：
10.4049/jimmunol.1900125
复制
发表时间：
2019-07-01
影响因子：
4.4
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
--
作者：
Luo, Yuewen;Liu, Yang;Zhang, Hui
激活诱导型胞苷脱氨酶(AID)启动Ig基因的类转换重组和体细胞超突变。AID的活性和蛋白水平受到多种机制的严格控制。在本研究中，我们发现CUL7E3泛素连接酶特异性地介导了AID泛素化。CUL7过表达或基因敲除可影响小鼠B淋巴细胞系CH12F3细胞中AID蛋白水平及随后的IgA类转换，从而影响AID的降解。进一步分析表明，CUL7通过与FBXW11形成复合体来介导AID泛素化。在CUL7(fl/fl)CD19(cre+)小鼠模型中，我们发现CUL7基因敲除显著增加了生发中心B细胞的AID蛋白水平，并增加了IgG1和IgA类的转换。总而言之，我们的结果揭示了一种严密控制AID蛋白水平的微妙调控机制。这一途径的操作可能有助于调节AID的丰度和Ig类转换的效率，因此是开发各种病原体疫苗(如HIV-1和流感病毒)的免疫佐剂的潜在靶点。
Activation-induced cytidine deaminase (AID) initiates class switch recombination and somatic hypermutation in Ig genes. The activity and protein levels of AID are tightly controlled by various mechanisms. In this study, we found that CUL7 E3 ubiquitin ligases specifically mediated AID ubiquitination. CUL7 overexpression or knockdown influenced the decay of AID, affecting AID protein levels and subsequently IgA class switching in CH12F3 cells, a mouse B lymphocyte cell line. Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7(fl/fl) CD19(cre+)mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. The manipulation of this pathway may be useful for regulating AID abundance and efficiency of Ig class switching and is therefore a potential target for developing immunologic adjuvants for vaccines of various pathogens such as HIV-1 and influenza viruses.