METTL18-catalyzed histidine methylation of YTHDF2 promotes mRNA stability.

RNA N6-methyladenosine (m6A), as the most prevalent and abundant RNA modification on mRNAs, plays indispensable roles in biological processes and development by modulating the fate of target RNAs. However, whether other METTL proteins, besides dominant METTL3 and METTL14, participate in the intricate dynamic regulation of mRNA m6A remains elusive. Here, we reveal that METTL18 catalyzes the methylation of histidine within the YTHDF2 protein, which in turn facilitates the stability of m6A-modified RNAs. Mechanistically, METTL18 directly interacts with YTHDF2 and catalyzes the methylation of histidine at position 437 of YTHDF2, attenuating its binding to m6A-modified target RNAs, thereby safeguarding these RNAs from degradation. Our findings not only demonstrate the crucial roles of METTL family proteins but also deepen our understanding of the intricate regulatory dynamics of m6A modification.