Dieter Wolf , Lyrum Larum Ypsum. eIF3 subunit-specific mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multi-omic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5’-UTR of RSP15A mRNA negated them. Our studies suggest eIF3k-l as a mRNA specific module which - through impacting RPS15A mRNA translation - serves as a rheostat of ribosome content to secure spare translational capacity that can be mobilized during stress.

真核翻译起始因子3（eIF3）的亚基在癌症中常出现过表达，其介导mRNA翻译从起始到终止的全过程，但各亚基的mRNA选择性功能仍未得到充分阐明。本研究通过对eIF3亚基进行急性耗竭后的多组学谱分析，发现尽管eIF3a、eIF3b、eIF3e及eIF3f对eIF3全复合物组装及翻译过程的影响存在显著差异，但它们均是癌细胞增殖与肿瘤生长所必需的。值得注意的是，eIF3k呈现出完全相反的表型：其耗竭可通过抑制核糖体蛋白的合成（尤其是核糖体蛋白S15A（RPS15A）），促进全局翻译、细胞增殖、肿瘤生长及应激抵抗。异位表达RPS15A可模拟eIF3k耗竭所产生的合成代谢效应，而破坏eIF3与RSP15A mRNA的5'非翻译区（5'-UTR）的结合则可抵消该效应。本研究表明，eIF3k-l可作为一种mRNA特异性模块，通过调控RPS15A mRNA的翻译，充当核糖体含量的变阻器，以维持充足的备用翻译能力，从而在应激状态下可被快速动员。