Grande Rebecca C, Lin Chia-Ching, Cammer Michael, Emesom Ebube D, Khurram Maaz Asher, Boutell Chris, Denes Lance T, Lionnet Timothée, Wilson Angus C, Mohr Ian
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
Microscopy Laboratory, Division of Advanced Research Technologies, New York University School of Medicine, New York, NY 10016, USA.
Cell Rep. 2025 Jul 22;44(7):115826. doi: 10.1016/j.celrep.2025.115826. Epub 2025 Jun 24.
The factors that install and recognize N-methyladenosine (mA) on RNA to regulate gene expression are well characterized, but how their spatial organization responds to physiological stress, including infection, is unclear. Here, we show that human cytomegalovirus (HCMV) infection induces accumulation of mA methyltransferase subunits, including WTAP, together with nuclear mA reader YTHDC1, into distinctive, membraneless nuclear bodies (NBs) overlapping with incoming virus genomes and immediate-early (IE) RNA transcripts. De novo assembly and integrity of these DNA-associated, IE, virus-activated NBs requires RNAPII transcription, METTL3 mA methyltransferase activity, and mA recognition by YTHDC1, but not new protein synthesis. Depleting YTHDC1 or WTAP limits the accumulation of critical HCMV RNAs required for virus DNA replication, interfering with virus reproduction. This reveals a surprising strategy whereby a discrete sub-nuclear RNA biogenesis compartment replete with RNAPII and mA modification components is swiftly consolidated in proximity to infecting HCMV genomes to initialize and sustain virus gene expression.
在RNA上安装并识别N-甲基腺苷（mA）以调节基因表达的相关因子已得到充分表征，但它们的空间组织如何响应包括感染在内的生理应激尚不清楚。在此，我们表明，人类巨细胞病毒（HCMV）感染会诱导包括WTAP在内的mA甲基转移酶亚基与核内mA阅读器YTHDC1一起积累，形成与进入的病毒基因组和立即早期（IE）RNA转录本重叠的独特无膜核体（NBs）。这些与DNA相关的、IE、病毒激活的NBs的从头组装和完整性需要RNA聚合酶II（RNAPII）转录、METTL3 mA甲基转移酶活性以及YTHDC1对mA的识别，但不需要新的蛋白质合成。耗尽YTHDC1或WTAP会限制病毒DNA复制所需的关键HCMV RNA的积累，从而干扰病毒繁殖。这揭示了一种惊人的策略，即一个充满RNAPII和mA修饰成分的离散亚核RNA生物合成区室会在感染的HCMV基因组附近迅速整合，以启动和维持病毒基因表达。
