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

A. Herrmannová, J. Jelínek, K. Pospíšilová, F. Kerényi, T. Vomastek, K. Watt, J. Brábek, MP. Mohammad, S. Wagner, I. Topisirovic, LS. Valášek

. 2024 ; 13 (-) : . [pub] 20241104

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003532

Grantová podpora
19-25821X Grantová Agentura České Republiky
Praemium Academiae Akademie Věd České Republiky
CZ.02.01.01/00/22_008/0004575 Ministerstvo Školství, Mládeže a Tělovýchovy
19-08013S Grantová Agentura České Republiky
Senior Investigator award Fonds de Recherche du Québec - Santé
LM2023055 The Ministry of Education, Youth and Sports
LX22NPO5102 European Union

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.

Citace poskytuje Crossref.org

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