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

Haoran Duan1, Siqiong Zhang1, Yoram Zarai2

  • 1State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.

The EMBO Journal
|May 8, 2023
PubMed

Insights

The eukaryotic initiation factor 3 (eIF3) complex controls protein synthesis. Researchers found that eIF3k subunit depletion boosts cancer cell growth by increasing ribosome production, revealing a new therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • The eukaryotic initiation factor 3 (eIF3) complex is crucial for mRNA translation.
  • Overexpression of eIF3 subunits is common in various cancers.
  • The specific roles of individual eIF3 subunits in mRNA selection and cancer progression are not well understood.

Purpose of the Study:

  • To investigate the mRNA-selective functions of individual eIF3 subunits.
  • To determine the role of eIF3 subunits in cancer cell proliferation and tumor growth.
  • To elucidate the mechanism by which eIF3k influences translation and cellular processes.

Main Methods:

  • Multiomic profiling of cells with acute depletion of eIF3 subunits.
  • Analysis of eIF3 holo-complex formation and global translation rates.
  • Investigation of cancer cell proliferation, tumor growth, and stress resistance.
  • RNA immunoprecipitation and reporter assays to study eIF3 binding to mRNA.
  • Mathematical modeling to understand regulatory mechanisms.

Main Results:

  • Depletion of eIF3a, b, e, and f subunits differentially affected eIF3 complex formation and translation but were all essential for cancer cell proliferation.
  • eIF3k depletion unexpectedly promoted global translation, cell proliferation, tumor growth, and stress resistance.
  • eIF3k depletion repressed the synthesis of ribosomal proteins, particularly RPS15A, and this effect was mediated by eIF3 binding to the 5'-UTR of RPS15A mRNA.
  • eIF3k and eIF3l subunits were selectively downregulated under endoplasmic reticulum and oxidative stress conditions.

Conclusions:

  • The eIF3k-l module acts as a specific regulator of RPS15A translation.
  • This module controls ribosome biogenesis, potentially maintaining translational capacity during stress.
  • Targeting the eIF3k-l module offers a potential strategy for cancer therapy.
Keywords:
RPS15Acancer growth controlmRNA selectivityribosome contenttranslation initiation factor 3

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