Department of Biology, Stanford University, Stanford, CA 94305, USA.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mol Cell. 2024 May 2;84(9):1753-1763.e7. doi: 10.1016/j.molcel.2024.02.037. Epub 2024 Mar 19.
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-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.
真核延伸因子 2 （eEF2）的翻译后修饰（PTMs）可以深刻影响 mRNA 的翻译动力学。然而，由 FAM86A 酶催化的翻译后修饰 eEF2K525 三甲基化（eEF2K525me3）的生理功能是未知的。在这里，我们发现 FAM86A 对 eEF2 的甲基化调节新生延伸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，建模为 K525me3 以促进易位过程中有效 eEF2-核糖体结合。在 LUAD 细胞中 FAM86A 的耗竭导致 80S 单核糖体积累和 mRNA 翻译抑制。FAM86A 在 LUAD 中过度表达，并且随着 LUAD 疾病阶段的进展，eEF2K525me3 水平增加。FAM86A 敲低可减弱 LUAD 细胞增殖，并且抑制 FAM86A-eEF2K525me3 轴可抑制癌症细胞和患者来源的 LUAD 异种移植在体内的生长。最后，FAM86A 消融在 KRAS 驱动的 LUAD 小鼠模型中强烈抑制肿瘤生长并延长生存。因此，我们的工作揭示了一种 eEF2 甲基化介导的 mRNA 翻译延伸调节节点，并将 FAM86A 作为 LUAD 的病因因子。
