Protein synthesis plays a major role in homeostasis and when dysregulated leads to various pathologies including cancer. To this end, imbalanced expression of eukaryotic translation initiation factors (eIFs) is not only a consequence but also a driver of neoplastic growth. eIF3 is the largest, multi-subunit translation initiation complex with a modular assembly, where aberrant expression of one subunit generates only partially functional subcomplexes. To comprehensively study the effects of eIF3 remodeling, we contrasted the impact of eIF3d, eIF3e or eIF3h depletion on the translatome of HeLa cells using Ribo-seq. Depletion of eIF3d or eIF3e, but not eIF3h reduced the levels of multiple components of the MAPK signaling pathways. Surprisingly, however, depletion of all three eIF3 subunits increased MAPK/ERK pathway activity. Depletion of eIF3e and partially eIF3d also increased translation of TOP mRNAs that encode mainly ribosomal proteins and other components of the translational machinery. Moreover, alterations in eIF3 subunit stoichiometry were often associated with changes in translation of mRNAs containing short uORFs, as in the case of the proto-oncogene MDM2 and the transcription factor ATF4. Collectively, perturbations in eIF3 subunit stoichiometry exert specific effect on the translatome comprising signaling and stress-related transcripts with complex 5' UTRs that are implicated in homeostatic adaptation to stress and cancer.

Laboratory of Bioinformatics Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Cell Signaling Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Regulation of Gene Expression Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Lady Davis Institute Gerald Bronfman Department of Oncology Department of Biochemistry Division of Experimental Medicine McGill University Montréal Canada

Lady Davis Institute Laboratory of Cancer Cell Invasion Faculty of Science Charles University Prague Czech Republic

Science for Life Laboratory Department of Oncology Pathology Karolinska Institutet Solna Sweden

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doi: 10.1101/2023.06.29.547003 PubMed

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doi: 10.7554/eLife.95846.1 PubMed

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doi: 10.7554/eLife.95846.2 PubMed

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Stem-loop-induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control

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