The Tumor Virology Program, Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
J Virol. 2024 Jul 23;98(7):e0054824. doi: 10.1128/jvi.00548-24. Epub 2024 Jun 12.
Most mature B-cell malignancies originate from the 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 BCL6 protein levels were dramatically decreased in Epstein-Barr virus (EBV)-positive lymphoblastoid cell lines and Burkitt's lymphoma cell lines. Notably, BCL6 degradation was significantly enhanced in the presence of both EBNA3C and FBXO11. Furthermore, the amino-terminal domain of EBNA3C, which contains residues 50-100, interacts directly with FBXO11. The expression of EBNA3C and FBXO11 resulted in a significant induction of cell proliferation. Furthermore, BCL6 protein expression levels were regulated by EBNA3C via the Skp Cullin Fbox (SCF) complex, which mediated its ubiquitylation, and knockdown of FBXO11 suppressed the transformation of lymphoblastoid cell lines. These data provide new insights into the function of EBNA3C in B-cell transformation during GC reaction and raise the possibility of developing new targeted therapies against EBV-associated cancers.
The novel revelation in our study involves the suppression of BCL6 expression by the essential Epstein-Barr virus (EBV) antigen EBNA3C, shedding new light on our current comprehension of how EBV contributes to lymphomagenesis by impeding the germinal center reaction. It is crucial to note that while several EBV latent proteins are expressed in infected cells, the collaborative mechanisms among these proteins in regulating B-cell development or inducing B-cell lymphoma require additional investigation. Nonetheless, our findings carry significance for the development of emerging strategies aimed at addressing EBV-associated cancers.
大多数成熟 B 细胞恶性肿瘤起源于生发中心 (GC) B 细胞的恶性转化。GC 反应似乎在恶性转化中起作用，GC 反应中的一个主要参与者是 BCL6，是该过程的关键调节剂。我们现在证明，EB 病毒 (EBV) 阳性淋巴母细胞系和伯基特淋巴瘤细胞系中 BCL6 蛋白水平显著降低。值得注意的是，在存在 EBNA3C 和 FBXO11 的情况下，BCL6 降解明显增强。此外，EBNA3C 的氨基末端结构域含有残基 50-100，与 FBXO11 直接相互作用。EBNA3C 和 FBXO11 的表达导致细胞增殖显著诱导。此外，EBNA3C 通过 Skp Cullin Fbox (SCF) 复合物调节 BCL6 蛋白表达水平，该复合物介导其泛素化，并且 FBXO11 的敲低抑制了淋巴母细胞系的转化。这些数据为 EBNA3C 在 GC 反应期间 B 细胞转化中的功能提供了新的见解，并提出了开发针对 EBV 相关癌症的新靶向治疗的可能性。
我们研究中的新发现涉及到必需的 Epstein-Barr 病毒 (EBV) 抗原 EBNA3C 对 BCL6 表达的抑制，这为我们目前对 EBV 通过阻碍生发中心反应促进淋巴瘤发生的理解提供了新的视角。需要注意的是，虽然感染细胞中表达了几种 EBV 潜伏蛋白，但这些蛋白在调节 B 细胞发育或诱导 B 细胞淋巴瘤中的协同机制仍需要进一步研究。尽管如此，我们的发现对于开发针对 EBV 相关癌症的新兴策略具有重要意义。
