Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides—besides transcription—an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP—together with the RBM4 splicing factor—in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.

中文翻译：

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爱泼斯坦-巴尔病毒 (EBV) 早期感染人原代 B 淋巴细胞期间选择性剪接的调节：病毒 EBNA-LP 蛋白的新功能

爱泼斯坦-巴尔病毒 (EBV) 是一种与全世界人类癌症相关的人类疱疹病毒。在体外，该病毒有效地感染静止的人 B 淋巴细胞并诱导其持续增殖。这个过程伴随着细胞基因转录的全局重编程。然而，关于 EBV 感染对可变剪接调节的影响知之甚少，可变剪接是一种在细胞命运决定中起重要作用的关键机制，并且在癌症中经常被解除调节。在这项研究中，我们对静息 B 淋巴细胞的 EBV 感染期间的细胞 mRNA 剪接变体表达进行了系统的时间分辨分析。我们的结果表明，可变剪接变体表达的主要修饰早在感染后的第 1 天就出现了，这表明剪接调节在 B 细胞活化和增殖开始时提供了一种额外的基因表达调节机制——除了转录。我们还报告了病毒蛋白 EBNA2 和 EBNA-LP 在调节特定可变剪接事件中的作用，并揭示了 EBNA-LP 与 RBM4 剪接因子在两个重要的可变剪接调节中的先前未知功能分别是细胞增殖和凋亡的调节剂，NUMB 和 BCL-X。