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Perturbations in eIF3 subunit stoichiometry alter expression of ribosomal proteins and key components of the MAPK

Anna Herrmannová1, Jan Jelínek2, Klára Pospíšilová1

  • 1Laboratory of Regulation of Gene Expression, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.

Elife
|November 4, 2024
PubMed

Insights

Altering eukaryotic translation initiation factor 3 (eIF3) subunits impacts cell signaling and stress responses. Specific eIF3 subunit depletion affects the translatome, influencing cancer-related gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Protein synthesis is crucial for cellular homeostasis; its dysregulation contributes to pathologies like cancer.
  • Imbalanced expression of eukaryotic translation initiation factors (eIFs) drives neoplastic growth.
  • eIF3, a large, multi-subunit complex, exhibits modular assembly; altered subunit expression yields partially functional subcomplexes.

Purpose of the Study:

  • To investigate the impact of specific eIF3 subunit depletion (eIF3d, eIF3e, eIF3h) on the cellular translatome.
  • To understand how eIF3 subunit stoichiometry alterations affect signaling pathways and stress-related transcripts.

Main Methods:

  • Utilized Ribo-seq (ribosome profiling) in HeLa cells to analyze the translatome.
  • Systematically depleted individual eIF3 subunits (eIF3d, eIF3e, eIF3h) to observe downstream effects.

Main Results:

  • Depletion of eIF3d or eIF3e, but not eIF3h, reduced MAPK signaling pathway components.
  • Depletion of all three studied eIF3 subunits paradoxically increased MAPK/ERK pathway activity.
  • eIF3e and partial eIF3d depletion increased translation of TOP mRNAs; alterations affected translation of mRNAs with short uORFs (e.g., MDM2, ATF4).

Conclusions:

  • Perturbations in eIF3 subunit stoichiometry have specific effects on the translatome, including signaling and stress-related transcripts.
  • These findings highlight the role of eIF3 complex integrity in regulating gene expression relevant to homeostatic adaptation and cancer.
Keywords:
MAPK pathwayeIF3geneticsgenomicshumanribosomal proteinsribosometranslationtranslational control

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