Division of Pathogenesis of Virus Associated Tumors, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
INSERM, German Cancer Research Centre (DKFZ), Heidelberg 69120, Germany.
Proc Natl Acad Sci U S A. 2021 Oct 26;118(43). doi: 10.1073/pnas.2115508118.
The Epstein-Barr virus (EBV) transforms resting B cells and is involved in the development of B cell lymphomas. We report here that the viral noncoding RNA EBER2 accelerates B cell growth by potentiating expression of the UCHL1 deubiquitinase that itself increased expression of the Aurora kinases and of cyclin B1. Importantly, this effect was also visible in Burkitt's lymphoma cells that express none of the virus's known oncogenes. Mechanistically, EBER2 bound the UCHL1 messenger RNA (mRNA), thereby bringing a protein complex that includes PU.1, a UCHL1 transactivator, to the vicinity of its promoter. Although the EBV oncogene LMP1 has been suggested to induce UCHL1, we show here that EBER2 plays a much more important role to reach significant levels of the deubiquitinase in infected cells. However, some viruses that carried a polymorphic LMP1 had an increased ability to achieve full UCHL1 expression. This work identifies a direct cellular target of a viral noncoding RNA that is likely to be central to EBV's oncogenic properties.
爱泼斯坦-巴尔病毒（EBV）可转化静止 B 细胞，并参与 B 细胞淋巴瘤的发生。我们在此报道，病毒非编码 RNA EBER2 通过增强 UCHL1 去泛素化酶的表达来加速 B 细胞生长，而 UCHL1 本身则增加了 Aurora 激酶和细胞周期蛋白 B1 的表达。重要的是，这种效应在表达病毒已知致癌基因的伯基特淋巴瘤细胞中也可见。从机制上讲，EBER2 结合 UCHL1 信使 RNA（mRNA），从而将包括 PU.1 在内的蛋白质复合物带到其启动子附近，PU.1 是 UCHL1 的转录激活因子。虽然 EBV 癌基因 LMP1 被认为可以诱导 UCHL1，但我们在此表明，EBER2 在感染细胞中发挥更重要的作用，以达到去泛素化酶的显著水平。然而，一些携带多态性 LMP1 的病毒具有增加的完全表达 UCHL1 的能力。这项工作确定了病毒非编码 RNA 的直接细胞靶标，这可能是 EBV 致癌特性的核心。
