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, P. R. China.
Department of Temporomandibular Joint Surgery, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, P. R. China.
J Biol Chem. 2021 Jan-Jun;296:100547. doi: 10.1016/j.jbc.2021.100547. Epub 2021 Mar 16.
N6-methyladenosine (mA) is among the most abundant mRNA modifications, particularly in eukaryotes, and is found in mammals, plants, and even some viruses. Although essential for the regulation of many biological processes, the exact role of mA modification in virus-host interaction remains largely unknown. Here, using mA -immunoprecipitation and sequencing, we find that Epstein-Barr virus (EBV) infection decreases the mA modification of transcriptional factor KLF4 mRNA and subsequently increases its protein level. Mechanistically, EBV immediate-early protein BZLF1 interacts with the promoter of mA methyltransferase METTL3, inhibiting its expression. Subsequently, the decrease of METTL3 reduces the level of KLF4 mRNA mA modification, preventing its decay by the mA reader protein YTHDF2. As a result, KLF4 protein level is upregulated and, in turn, promotes EBV infection of nasopharyngeal epithelial cells. Thus, our results suggest the existence of a positive feedback loop formed between EBV and host molecules via cellular mRNA mA levels, and this feedback loop acts to facilitate viral infection. This mechanism contains multiple potential targets for controlling viral infectious diseases.
N6-甲基腺苷（mA）是最丰富的 mRNA 修饰物之一，尤其在真核生物中，在哺乳动物、植物甚至某些病毒中都有发现。尽管 mA 修饰对于许多生物过程的调节至关重要，但 mA 修饰在病毒-宿主相互作用中的确切作用在很大程度上仍不清楚。在这里，我们使用 mA 免疫沉淀和测序发现，EB 病毒（EBV）感染会降低转录因子 KLF4 mRNA 的 mA 修饰，随后增加其蛋白水平。从机制上讲，EBV 早期蛋白 BZLF1 与 mA 甲基转移酶 METTL3 的启动子相互作用，抑制其表达。随后，METTL3 的减少降低了 KLF4 mRNA mA 修饰的水平，防止其被 mA 读蛋白 YTHDF2 降解。结果，KLF4 蛋白水平上调，进而促进 EBV 感染鼻咽上皮细胞。因此，我们的研究结果表明，通过细胞 mRNA mA 水平，EBV 和宿主分子之间存在一个正反馈环，该反馈环有助于病毒感染。该机制包含多个控制病毒感染性疾病的潜在靶点。
