Gammaherpesvirus miRNA suppression of EWSR1 in GC B cell infection and lymphomagenesis

总结 转化人类γ疱疹病毒、EB病毒和卡波西肉瘤- 相关疱疹病毒（KSHV）与多种类型的恶性肿瘤的发生有关， 包括广泛的生发中心（GC）衍生的B细胞淋巴瘤。这些病毒建立了 通过感染幼稚B细胞并独立驱动这些细胞，在B细胞中终身潜伏感染 利用GC反应增殖并分化为静息记忆B细胞。因此，在本发明中， 感染的B细胞通过GC的转运对于γ疱疹病毒生物学是关键的。尽管如此， γ-疱疹病毒操纵GC反应的具体机制， 对GC衍生的B细胞淋巴瘤的作用还不完全清楚。病毒编码的微小RNA 被γ疱疹病毒用来操纵感染的细胞。重要的是， 这些miRNAs的特异性体内功能和生物学相关性几乎完全 由于人类病毒严格的物种特异性，因此未知。鼠γ疱疹病毒68 MHV 68、MuHV-4与EBV和KSHV在遗传和致病上相关，并引起B细胞 具有人类γ疱疹病毒恶性肿瘤特征的淋巴瘤。我们最近 证明MHV 68 miRNA miR-7- 5 p抑制多功能宿主蛋白EWSR 1 （尤文肉瘤断点蛋白1）促进GC B细胞的潜伏感染。值得注意的是， EWSR 1在γ疱疹病毒感染和GC B细胞生物学中的作用完全 未知在这里的工作中，我们将测试EWSR 1抑制对于 生殖中心B细胞的增殖性扩增，定义了 EWSR 1抑制有助于生发中心B细胞扩增，并定义了这种贡献 miR-7- 5 p介导的EWSR 1对B细胞淋巴瘤发生的抑制作用。

Summary The transforming human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma- associated herpesvirus (KSHV) are linked to the development of multiple types of malignancies, including a wide range of germinal center (GC)-derived B cell lymphomas. These viruses establish lifelong latent infections in B cells by infecting naïve B cells and driving those cells, independent of antigen, to utilize GC reactions to proliferate and differentiate into resting memory B cells. Thus, the transit of infected B cells through the GC is critical to gammaherpesvirus biology. Despite this, the specific mechanisms by which gammaherpesviruses manipulate GC reactions and contribute to GC-derived B cell lymphomas are not fully understood. Virus-encoded microRNAs (miRNAs) are employed by gammaherpesviruses to manipulate infected cells. Importantly though, the specific in vivo functions and biological relevance of these miRNAs are almost completely unknown due to the strict species specificity of the human viruses. Murine gammaherpesvirus 68 (MHV68, MuHV-4) is genetically and pathogenically related to EBV and KSHV, and causes B cell lymphomas with features of human gammaherpesvirus malignancies. We have recently demonstrated that MHV68 miRNA miR-7-5p repression of the multifunctional host protein EWSR1 (Ewing sarcoma breakpoint protein 1) promotes latent infection of GC B cells. Notably though, the roles of EWSR1 in both gammaherpesvirus infection and GC B cell biology are completely unknown. In work here, we will test the hypothesis that EWSR1 repression is critical for proliferative expansion of germinal center B cells, define the molecular mechanism by which EWSR1 repression contributes to germinal center B cell expansion, and define the contribution of miR-7-5p-mediated EWSR1 repression to B cell lymphomagenesis.