MCTS2 and distinct eIF2D roles in uORF-dependent translation regulation revealed by in vitro re-initiation assays.

Détails

ID Serval
serval:BIB_49566FFF461F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
MCTS2 and distinct eIF2D roles in uORF-dependent translation regulation revealed by in vitro re-initiation assays.
Périodique
The EMBO journal
Auteur⸱e⸱s
Meurs R., De Matos M., Bothe A., Guex N., Weber T., Teleman A.A., Ban N., Gatfield D.
ISSN
1460-2075 (Electronic)
ISSN-L
0261-4189
Statut éditorial
Publié
Date de publication
02/2025
Peer-reviewed
Oui
Volume
44
Numéro
3
Pages
854-876
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Ribosomes scanning from the mRNA 5' cap to the start codon may initiate at upstream open reading frames (uORFs), decreasing protein biosynthesis. Termination at a uORF can lead to re-initiation, where 40S subunits resume scanning and initiate another translation event downstream. The noncanonical translation factors MCTS1-DENR participate in re-initiation at specific uORFs, but knowledge of other trans-acting factors or uORF features influencing re-initiation is limited. Here, we establish a cell-free re-initiation assay using HeLa lysates to address this question. Comparing in vivo and in vitro re-initiation on uORF-containing reporters, we validate MCTS1-DENR-dependent re-initiation in vitro. Using this system and ribosome profiling in cells, we found that knockdown of the MCTS1-DENR homolog eIF2D causes widespread gene deregulation unrelated to uORF translation, and thus distinct to MCTS1-DENR-dependent re-initiation regulation. Additionally, we identified MCTS2, encoded by an Mcts1 retrogene, as a DENR partner promoting re-initiation in vitro, providing a plausible explanation for clinical differences associated with DENR vs. MCTS1 mutations in humans.
Mots-clé
Humans, HeLa Cells, Open Reading Frames, Protein Biosynthesis, Peptide Chain Initiation, Translational, Ribosomes/metabolism, Ribosomes/genetics, Gene Expression Regulation, Membrane Proteins/metabolism, Membrane Proteins/genetics, Neoplasm Proteins/metabolism, Neoplasm Proteins/genetics, Cell-Free System, RNA, Messenger/genetics, RNA, Messenger/metabolism, Oncogene Proteins, Eukaryotic Initiation Factor-2, Cell Cycle Proteins, Eukaryotic Initiation Factors, DENR-MCTS1, In Vitro Translation, Re-Initiation, eIF2D, uORF
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/01/2025 14:54
Dernière modification de la notice
15/02/2025 9:49
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