eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth in vivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRAS^G12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.

eEF2 翻译后修饰 (PTM) 可以深刻影响 mRNA 翻译动态。然而，eEF2K525 三甲基化 (eEF2K525me3)（一种由 FAM86A 酶催化的 PTM）的生理功能尚不清楚。在这里，我们发现 eEF2 的 FAM86A 甲基化调节新生伸长，以促进蛋白质合成和肺腺癌 (LUAD) 发病机制。 FAM86A 的主要生理底物是 eEF2，K525me3 被建模以促进易位期间有效的 eEF2-核糖体接合。 LUAD 细胞中 FAM86A 缺失会导致 80S 单体积累和 mRNA 翻译抑制。FAM86A在 LUAD 中过度表达，并且 eEF2K525me3 水平随着 LUAD 疾病阶段的进展而增加。 FAM86A 敲低会减弱 LUAD 细胞增殖，抑制 FAM86A-eEF2K525me3 轴会抑制癌细胞和患者体内LUAD 异种移植物的生长。最后，FAM86A消融可强烈减弱 KRAS ^G12C驱动的 LUAD 小鼠模型中的肿瘤生长并延长生存期。因此，我们的工作揭示了 eEF2 甲基化介导的 mRNA 翻译延伸调节节点，并提名 FAM86A 作为 LUAD 的病因。