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.

Synopsis

Are there mRNA-selective functions of individual eIF3 subunits? Here, multiomic profiling upon acute depletion of eIF3 subunits uncovers eIF3k-l as an mRNA-specific module that serves as a rheostat of ribosome content, securing spare translational capacity that can be mobilized during stress.

• Acute depletion of eIF3 subunits has subunit-selective impact on holo-eIF3 architecture.

• eIF3k depletion uniquely causes increased tumor growth and ribosome content.

• eIF3k depletion boosts the translation of RPS15A mRNA through an eIF3-binding site in the 5′-UTR.

• eIF3k and eIF3l are selectively downregulated by cellular stress, thus promoting cell survival.

Link: https://www.embopress.org/doi/full/10.15252/embj.2022112362