Laboratory of Molecular and Cellular Virology, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
HIV/AIDS Workgroup (CHAIR), Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Nucleic Acids Res. 2022 Feb 28;50(4):2302-2318. doi: 10.1093/nar/gkac062.
During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that deposition of N6-methyladenosine (m6A) regulates full-length RNA packaging. While m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5'-UTR that have a crucial functional role in m6A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes.
在逆转录病毒复制过程中，全长 RNA 既可以作为 mRNA，也可以作为基因组 RNA。然而，HIV-1 Gag 蛋白选择将两种 RNA 分子包装到新形成的病毒粒子中的机制仍知之甚少。在这里，我们证明 N6-甲基腺苷（m6A）的沉积调节全长 RNA 的包装。虽然全长 RNA 上的 METTL3/METTL14 沉积 m6A 与 Gag 合成增加和包装减少有关，但 FTO 介导的去甲基化促进全长 RNA 掺入病毒颗粒。有趣的是，HIV-1 Gag 与核内的 RNA 去甲基酶 FTO 相关，并有助于全长 RNA 的去甲基化。我们进一步鉴定了 5'-UTR 内的两个高度保守的腺苷，它们在 m6A 甲基化和全长 RNA 包装中具有关键的功能作用。总之，我们的数据提出了一种新的转录后修饰机制，允许选择用作病毒基因组的 HIV-1 全长 RNA 分子。
