Methylated eEF1A selectively decodes mRNA to shape cancer proteomes
Year: 2026
Type: article
Abstract: Although mRNA decoding efficiency influences protein synthesis, it remains unknown whether the translation elongation machinery harbours intrinsic mechanisms that selectively modulate codon decoding to shape proteomes. Here we show that METTL13-catalysed dimethylation of the elongation factor eEF1A at lysine 55 (eEF1AK55me2) enhances decoding of select codons, preferentially increasing pro-oncogenic protein synthesis to promote tumorigenesis and targeted therapy resistance. Proteomic profiling and single-molecule imaging reveal that eEF1AK55me2 increases decoding efficiency, particularly for under-represented codons with weak wobble-position base pairing. In cancer cells, METTL13 knockdown reduced translation of oncogenic mRNA enriched in eEF1AK55me2-dependent codons, including KRAS; synonymous recoding with eEF1AK55me2-independent codons reversed this effect. METTL13 loss inhibited the growth of KRASG12C inhibitor (sotorasib)-resistant lung adenocarcinoma syngeneic tumours and patient-derived xenografts. In relapsed autochthonous KRASG12C-driven lung adenocarcinoma, METTL13 ablation mitigated sotorasib resistance and significantly extended survival in vivo. Among patients receiving a KRASG12C inhibitor, inferred METTL13 activity was associated with inferior clinical response. These findings identify an eEF1AK55me2-mediated mRNA decoding mechanism promoting selective oncogenic protein synthesis and suggest METTL13 targeting may counteract KRAS-inhibitor resistance. The authors show that METTL13-mediated eEF1A K55 dimethylation enhances decoding of rare codons, boosting translation of oncogenic proteins including KRAS and promoting KRAS-inhibitor resistance in lung cancer.
Source: Nature Cell Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Defense, American Cancer Society, Cancer Prevention and Research Institute of Texas, Canada Research Chairs, Terry Fox Foundation, Cancerfonden, Knut och Alice Wallenbergs Stiftelse, Radiumhemmets Forskningsfonder, National Institutes of Health, Canadian Institutes of Health Research, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Imaging Protein Synthesis on the Ribosome using Single-Molecule FRET, Mechanisms of translational output control in pancreatic cancer, Role of SETD5 in Chromatin Regulation and Tumorigenesis, Role of NSD3 in regulation of cancer pathogenesis, Tumor cell lineage diversity and composition in gastric cancer progression and therapy resistance, Viral modulation of epitranscriptomic mechanisms, Function of Protein Methylation in Chromatin and Signaling Regulation, Mechanisms of action and therapeutic targeting of the CARM1-NFIB axis in small cell lung cancer, Therapeutic Targeting of NSD2 in Lung Adenocarcinoma, Training in Basic Research on Aging and Age-Related Disease, Quantitative mass spectrometry for comprehending epigenetic mechanisms in a new underlying neurological developmental disorder
OpenAlex ID: W7224227034