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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 multiomic 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. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress.

Original languageEnglish
Article numbere112362
JournalEMBO Journal
Volume42
Issue number12
DOIs
StatePublished - 15 Jun 2023

Funding

FundersFunder number
DAW
Mass Spectrometry Facility of the School of Pharmaceutical Sciences
Xiamen University Department of Life Sciences & Human Health
Zimin Institute for Engineering Solutions
Science and Technology Projects of Fujian Province2021Y0002
European Research CouncilPACA‐MET
Deutsche ForschungsgemeinschaftSFB1321, DFG RA1629/2‐1, SFB1335, DFG RA1629/4‐1
National Natural Science Foundation of China
Natural Science Foundation of Fujian Province2018J01053
Deutsche Krebshilfe70114314
Xiamen University81773771, 31770813
Fundamental Research Funds for the Central Universities20720220053
Deutschen Konsortium für Translationale Krebsforschung

    Keywords

    • RPS15A
    • cancer growth control
    • mRNA selectivity
    • ribosome content
    • translation initiation factor 3

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