新型病毒非编码RNA LMP2A-IT1促进EBV的裂解复制

文献信息

中文摘要

背景： EB病毒（EBV）被认为是首个人类肿瘤病毒，并在病因学上与一系列恶性肿瘤和自身免疫性疾病相关。EBV裂解复制对发病机制有重要贡献，但使病毒能在宿主细胞内高效复制的病毒组分仍未完全阐明。
方法： 在此，我们从糖RNA样本中鉴定出一种此前未知的EBV非编码RNA（ncRNA），并将其命名为LMP2A-IT1。该病毒ncRNA在多种EBV感染的细胞系、外泌体以及EBV阳性鼻咽癌组织中均可稳定检测到，主要呈细胞质分布。
结果： 功能分析显示，EBV裂解复制过程中LMP2A-IT1的诱导会主动驱动裂解周期，形成自我放大的正反馈环路。机制上，LMP2A-IT1似乎激活炎症反应，随后上调BZLF1——EBV裂解级联反应的主调控因子——以促进裂解进程。
结论： 总之，我们的发现表明LMP2A-IT1是EBV为实现强效复制而部署的一种此前未被认识的病毒因子。据我们所知，这是首次报道带有糖基化修饰的病毒RNA，从而拓展了糖RNA的图谱。此外，本研究为EBV复制提供了新的机制见解，并为EBV相关疾病提供了潜在的生物标志物和治疗靶点。

英文摘要

The Epstein-Barr virus (EBV) is recognized as the first human tumor virus and etiologically linked to a spectrum of malignancies and autoimmune diseases. EBV lytic replication contributes substantially to pathogenesis, but the viral components that enable efficient replication within host cells remain incompletely understood. Here, we identified a previously unknown EBV non-coding RNA (ncRNA) from glycoRNA samples and designated it LMP2A-IT1. This viral ncRNA was consistently detected across multiple EBV-infected cell lines, in exosomes, and in EBV-positive nasopharyngeal carcinoma tissues, exhibiting a predominantly cytoplasmic distribution. Functional analyses reveal that the induction of LMP2A-IT1 during EBV lytic replication actively drives the lytic cycle, resulting in a self-amplifying positive feedback loop. Mechanistically, LMP2A-IT1 appears to activate an inflammatory response, which subsequently upregulates BZLF1, a master regulator of the EBV lytic cascade, to facilitate lytic progression. Together, our findings suggest that LMP2A-IT1 represents a previously unrecognized viral factor that EBV deploys to achieve robust replication. To our best knowledge, this is the first report of a viral RNA harboring glycosylation modifications, thereby expanding the glycoRNA landscape. Moreover, this study offers new mechanistic insights into EBV replication as well as a potential biomarker and therapeutic target for EBV-associated diseases.