Methylated eEF1A Selectively Decodes mRNA to Shape Cancer Proteomes

However, whether the translation elongation machinery harbors an intrinsic mechanism that selectively decodes codons, and how this shapes proteomes in homeostasis and disease, remains unknown. Here we find that METTL13-catalyzed dimethylation of the elongation factor eEF1A at lysine 55 (eEF1AK55me2) enhances decoding of select codons, thereby preferentially increasing synthesis of pro-oncogenic proteins to promote tumorigenesis and targeted therapy resistance.

Proteomic profiling and single-molecule imaging reveal that eEF1AK55me2 increases decoding efficiency, particularly for underrepresented codons with weak wobble-position base-pairing. In cancer cells, METTL13 knockdown reduced synthesis of oncogenic proteins, such as KRAS, encoded by genes enriched in eEF1AK55me2-dependent codons; synonymous recoding with eEF1AK55me2-independent codons reversed this effect. Loss of METTL13 inhibited growth of KRASG12C-inhibitor (sotorasib)-resistant syngeneic and patient-derived lung adenocarcinoma (LUAD) xenografts.