eIF3 mRNA selectivity profiling reveals eIF3k as a cancer‐relevant regulator of ribosome content

• DOI: 10.15252/embj.2022112362
• Publication Date: 2023-05-08T18:22:29Z
• Authors: Haoran Duan; Siqiong Zhang; Yoram Zarai; Rupert Öllinger; Yanmeng Wu; Li Sun; Cheng Hu; Yaohui He; Guiyou Tian; Roland Rad; Xiangquan Kong; Yabin Cheng; Tamir Tuller; Dieter A Wolf
• Keywords: Ribosome profiling

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual remain poorly defined. Using multiomic profiling upon acute depletion eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed their impact on holo-complex formation translation, they were each required for cancer cell proliferation tumor growth. Remarkably, eIF3k showed the opposite pattern with promoting global proliferation, growth, stress resistance through repressing synthesis ribosomal proteins, especially RPS15A. Whereas ectopic expression RPS15A mimicked anabolic effects depletion, disruption binding 5'-UTR RSP15A negated them. eIF3l selectively downregulated response endoplasmic reticulum oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, controlling serves rheostat ribosome content, possibly secure spare translational capacity can be mobilized during