Inhibition of the m6A mRNA methyltransferase complex by the alphaherpesvirus viral protein kinase US3

Chemical modifications of mRNA, the so-called epitranscriptome, have emerged as an additional layer of post-transcriptional regulation of gene expression. The most common epitranscriptomic modification, m6A, is generated by a large multi-subunit complex. Although the components that make up the m6A methyltransferase complex have been identified, it is currently largely unclear how the activity of this complex is regulated. Here we show that alphaherpesvirus kinases phosphorylate several components of the m6A methyltransferase complex, including METTL3, METTL14 and WTAP. Phosphorylation of these proteins correlates with inhibition of the m6A methyltransferase complex and a near complete loss of m6A levels in alphaherpesvirus-infected cells. Expression of the viral serine/threonine protein kinase US3 is necessary and sufficient for phosphorylation of METTL3 and METTL14 and inhibition of the m6A methyltransferase complex. Together, these findings provide the first evidence for phosphorylation that inactivates the m6A methyltransferase complex, in this case mediated by the viral US3 kinase.

mRNA的化学修饰，即所谓的表转录组，已成为基因表达转录后调控的额外层次。其中最常见的表转录组修饰，m6A，由一个大型多亚基复合物产生。尽管已识别出构成m6A甲基转移酶复合物的成分，但目前对其活性调控的机制尚不明确。本研究揭示，α-疱疹病毒激酶磷酸化m6A甲基转移酶复合物的多个组分，包括METTL3、METTL14和WTAP。这些蛋白质的磷酸化与m6A甲基转移酶复合物的抑制以及疱疹病毒感染细胞中m6A水平的几乎完全丧失相关。病毒丝氨酸/苏氨酸蛋白激酶US3的表达对于METTL3和METTL14的磷酸化以及m6A甲基转移酶复合物的抑制是必要且充分的。总之，这些发现首次提供了m6A甲基转移酶复合物被磷酸化而失活的证据，在此案例中，该过程由病毒US3激酶介导。