The Novel Viral Non‐Coding RNA LMP2A‐IT1 Promotes the Lytic Replication of EBV
Zheng‐Zhou Lu, Jun‐Fei Wu, Nannan Zhu, Ming‐Hui Yang, Le‐Le Zhang, Yuan‐Tao Liu, Wei‐Jun Chen, Jin‐Kun Tang, Jia‐Wei Ge, Chao‐Bo Lei, Tao Zhang, Yu Wang, Chao‐Yun Huang, Qian Zhong, Mu‐Sheng Zeng, Yan LiABSTRACT
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.