1. FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis.
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Francis, Joel William, Hausmann, Simone, Ikram, Sabeen, Yin, Kunlun, Mealey-Farr, Robert, Flores, Natasha Mahealani, Trinh, Annie Truc, Chasan, Tourkian, Thompson, Julia, Mazur, Pawel Karol, and Gozani, Or
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MESSENGER RNA , *POST-translational modification , *PROTEIN synthesis , *METHYLATION , *CARCINOGENESIS , *GENETIC translation - Abstract
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 KRASG12C-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. [Display omitted] • FAM86A physiologically generates eEF2K525me3 in diverse cellular and tissue samples • FAM86A-eEF2K525me3 pathway regulates elongation to promote protein synthesis • Generation of a facile KRAS.G12C GEMM to model lung cancer in vivo • Inhibition of FAM86A-eEF2K525me3 axis strongly suppresses lung cancer tumorigenesis FAM86A trimethylates the essential mRNA translation elongation factor eEF2 at K525 (eEF2Km525me3), a PTM of unknown function. Francis et al. show that FAM86A generation of eEF2K525me3 regulates the mRNA translation elongation step to promote global protein synthesis and lung cancer pathogenesis in vivo , including in a KRAS.G12C-driven GEM tumor model. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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