Divergent roles of nonsense-mediated RNA decay in oncovirus latency and reactivation

无意义介导的RNA衰退(NMD)是一种高度保守的细胞质量控制途径，可以降解许多突变或异常剪接的RNA转录本。最近文献中的报道将NMD过程与肿瘤的发生和转移联系起来，以复杂的，有时甚至是相互矛盾的方式。NMD通常被认为是一种肿瘤抑制途径，在癌症中经常下调，导致癌基因的高表达(有时是突变的)。另一方面，一些癌症似乎利用甚至增强了NMD系统来降解肿瘤抑制基因的转录，从而失调癌基因的表达，并导致癌细胞增殖增加。 EBV是一种普遍存在的人类病原体，感染了世界90%以上的人口，并与淋巴瘤、胃癌和鼻咽癌等癌症有关。通常，EBV在宿主B细胞中潜伏期持续存在，在此期间，有限的病毒基因表达保护病毒免受宿主免疫系统的攻击。周期性地，裂解周期的重新激活导致病毒接管宿主细胞并产生新的传染性病毒粒子，从而促进病毒的传播。有趣的是，在重新激活过程中表达的一些EBV RNA转录本似乎是NMD的靶标。我们的初步研究表明，EBV在裂解再激活过程中积极抑制宿主细胞的NMD，可能阻止病毒RNA转录本的降解，促进病毒蛋白翻译和病毒粒子的产生。相反，我们发现NMD通路在潜伏期是活跃的，在潜伏期，它可能促进细胞增殖，同时防止裂解重新激活。这两种截然相反的接触模式在EBV和宿主NMD之间形成了一种“阴阳”关系，这种关系在控制其两相感染策略方面发挥了关键作用。 在这个项目中，我们将研究这种新型的动态病毒界面与宿主系统，以确定EBV-NMD相互作用的机制基础，并确定其对病毒重新激活、病毒潜伏期和淋巴瘤细胞生长和增殖的功能影响。

Nonsense-mediated RNA Decay (NMD) is a highly conserved cellular quality control pathway that degrades many mutant or aberrantly spliced RNA transcripts. Reports in the literature have recently linked NMD processes to oncogenesis and metastasis, in complex and sometimes contradictory ways. Often considered a tumor suppressor pathway, NMD is frequently downregulated in cancers, resulting in higher expression of (sometimes mutated) oncogenes. On the other hand, some cancers appear to harness or even enhance the NMD system to degrade transcripts of tumor suppressor genes, dysregulating oncogene expression and leading to increased cancer cell proliferation. EBV is a ubiquitous human pathogen that infects more than 90% of the world’s population and is associated with cancers including lymphomas, gastric carcinoma and nasopharyngeal carcinoma. Typically, EBV persists in host B cells in a latent phase, during which time limited viral gene expression shields the virus from the host immune system. Periodically, reactivation of the lytic cycle leads to viral takeover of the host cell and production of new infectious virions, facilitating viral spread. Interestingly, some EBV RNA transcripts expressed during reactivation appear to be NMD targets. Our preliminary studies have revealed that EBV actively inhibits host cellular NMD during lytic reactivation, presumably preventing degradation of viral RNA transcripts and facilitating viral protein translation and virion production. In contrast, we find that the NMD pathway is active during the latency phase where it likely promotes cell proliferation while simultaneously preventing lytic reactivation. These two opposite modes of engagement form a sort of “yin and yang” relationship between EBV and host NMD that plays a key role in governing its biphasic infection strategy. With this project we will investigate this novel dynamic viral interface with a host system to determine the mechanistic underpinnings of EBV-NMD interactions and determine its functional impact on viral reactivation, viral latency and lymphoma cell growth and proliferation.