State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
EMBO Rep. 2021 Apr 7;22(4):e50128. doi: 10.15252/embr.202050128. Epub 2021 Feb 19.
N -methyladenosine (m A) modification of mRNA mediates diverse cellular and viral functions. Infection with Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma (NPC), 10% of gastric carcinoma, and various B-cell lymphomas, in which the viral latent and lytic phases both play vital roles. Here, we show that EBV transcripts exhibit differential m A modification in human NPC biopsies, patient-derived xenograft tissues, and cells at different EBV infection stages. m A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, which leads to the m A-dependent suppression of EBV infection and replication. Mechanistically, YTHDF1 hastens viral RNA decapping and mediates RNA decay by recruiting RNA degradation complexes, including ZAP, DDX17, and DCP2, thereby post-transcriptionally downregulating the expression of EBV genes. Taken together, our results reveal the critical roles of m A modifications and their reader YTHDF1 in EBV replication. These findings contribute novel targets for the treatment of EBV-associated cancers.
N6-甲基腺苷（m6A）修饰mRNA 介导多种细胞和病毒功能。 Epstein-Barr 病毒（EBV）感染与鼻咽癌（NPC）、10%的胃癌和各种 B 细胞淋巴瘤密切相关，其中病毒潜伏和裂解期都发挥着至关重要的作用。在这里，我们发现 EBV 转录本在人 NPC 活检组织、患者来源的异种移植组织和不同 EBV 感染阶段的细胞中表现出不同的 m6A 修饰。m6A 修饰的 EBV 转录本被 YTHDF1 蛋白识别并使其不稳定，从而导致 EBV 感染和复制的 m6A 依赖性抑制。从机制上讲，YTHDF1 通过招募 RNA 降解复合物（包括 ZAP、DDX17 和 DCP2）加速病毒 RNA 脱帽，并介导 RNA 衰变，从而在后转录水平下调 EBV 基因的表达。总之，我们的研究结果揭示了 m6A 修饰及其阅读器 YTHDF1 在 EBV 复制中的关键作用。这些发现为治疗 EBV 相关癌症提供了新的靶点。
