UPF1 promotes rapid degradation of m6A-containing RNAs. Boo et al.

N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic mRNAs and affects diverse RNA processing and metabolism. When YTHDF2, an m6A-recognizing protein, binds to m6A, it facilitates the destabilization of m6A-containing RNAs (m6A RNAs). Here, we demonstrate that upstream frameshift 1 (UPF1), a key factor for nonsense-mediated mRNA decay, interacts with YTHDF2, thereby triggering rapid degradation of m6A RNAs. The UPF1-mediated m6A RNA degradation depends on a specific interaction between UPF1 and N-terminal residues 101–168 of YTHDF2, UPF1 ATPase/helicase activities, and UPF1 interaction with proline-rich nuclear receptor coactivator 2 (PNRC2), a decapping-promoting factor preferentially involved in nonsense-mediated mRNA decay. Furthermore, transcriptome-wide analyses show that YTHDF2-bound mRNAs that are not substrates for HRSP12-RNase P/MRP–mediated endoribonucleolytic cleavage are destabilized with a higher dependency on UPF1. Collectively, our data indicate dynamic and multilayered regulation of the stability of m6A RNAs and highlight the multifaceted role of UPF1 in mRNA decay.

N6-甲基腺苷（m6A）是真核生物mRNA中最普遍的内部修饰，它影响着RNA的多种加工和代谢过程。当识别m6A的蛋白YTHDF2与m6A结合时，它促进了含有m6A的RNA（m6A RNA）的降解。在本研究中，我们展示了上游移码1（UPF1），一种关键的 nonsense介导的mRNA降解因子，与YTHDF2相互作用，从而触发m6A RNA的快速降解。UPF1介导的m6A RNA降解依赖于UPF1与YTHDF2氨基端101-168位残基的特定相互作用，UPF1的ATP酶/解旋酶活性，以及UPF1与脯氨酸富集的核受体辅激活因子2（PNRC2）的相互作用，PNRC2是一种优先参与nonsense介导的mRNA降解的剪接促进因子。此外，全转录组分析显示，YTHDF2结合的mRNA，若非HRSP12-RNase P/MRP介导的内切核糖核酸酶切割底物，其稳定性将因对UPF1的依赖性更高而降低。综上所述，我们的数据表明m6A RNA稳定性的动态和多层级调控，并突出了UPF1在mRNA降解中的多面性作用。