An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation

The latent EBV nuclear antigen 3C (EBNA3C) is required for transformation of primary human B lymphocytes. Most mature B-cell malignancies originate from malignant transformation of germinal center (GC) B-cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reaction is Bcl6, a key regulator of this process. We now demonstrate that EBNA3C contributes to B-cell transformation by targeted degradation of Bcl6. We show that EBNA3C can physically associate with Bcl6. Notably, EBNA3C expression leads to reduced Bcl6 protein levels in a ubiquitin-proteasome dependent manner. Further, EBNA3C inhibits the transcriptional activity of the Bcl6 promoter through interaction with the cellular protein IRF4. Bcl6 degradation induced by EBNA3C rescued the functions of the Bcl6-targeted downstream regulatory proteins Bcl2 and CCND1, which resulted in increased proliferation and G1-S transition. These data provide new insights into the function of EBNA3C in B-cell transformation during GC reaction, and raises the possibility of developing new targeted therapies against EBV-associated cancers.

潜伏EB病毒核抗原3C（EBNA3C）是原代人B淋巴细胞转化所必需的因子。绝大多数成熟B细胞恶性肿瘤起源于生发中心（germinal center，GC）B细胞的恶性转化。生发中心反应在恶性转化过程中发挥关键作用，其中该反应的核心调控蛋白为Bcl6。本研究证实，EBNA3C可通过靶向降解Bcl6参与B细胞转化。实验结果显示，EBNA3C能够与Bcl6发生物理结合。值得注意的是，EBNA3C的表达以泛素-蛋白酶体依赖的方式降低Bcl6的蛋白水平。进一步研究表明，EBNA3C通过与细胞蛋白干扰素调节因子4（IRF4）相互作用，抑制Bcl6启动子的转录活性。EBNA3C诱导的Bcl6降解可挽救Bcl6靶向的下游调控蛋白B细胞淋巴瘤因子2（Bcl2）与细胞周期蛋白D1（CCND1）的功能，进而促进细胞增殖与G1-S期转换。上述研究结果为EBNA3C在生发中心反应过程中参与B细胞转化的功能提供了新的见解，并为开发EB病毒相关癌症的新型靶向治疗方案提供了可能。