Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation

Autor: Kamiko R. Bressler, Joseph A. Ross, Nehal Thakor
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Eukaryotic Initiation Factor-1
Activating Transcription Factor 4
Catalysis
Article
Cell Line
lcsh:Chemistry
Inorganic Chemistry
03 medical and health sciences
upstream open reading frames (uORFs)
Eukaryotic translation
Peptide Initiation Factors
Eukaryotic initiation factor
Upstream open reading frame
eIF1A
Humans
Physical and Theoretical Chemistry
Eukaryotic Initiation Factors
Phosphorylation
RNA
Small Interfering
eukaryotic initiation factor 2α (eIF2α)
lcsh:QH301-705.5
Molecular Biology
Spectroscopy
eIF2
Chemistry
Organic Chemistry
ATF4
RNA-Binding Proteins
Translation (biology)
RNA-Directed DNA Polymerase
General Medicine
Eukaryotic Initiation Factor-2
Endonucleases
Computer Science Applications
Cell biology
030104 developmental biology
HEK293 Cells
lcsh:Biology (General)
lcsh:QD1-999
Polyribosomes
Protein Biosynthesis
eIF2A
eukaryotic initiation factor 5B (eIF5B)
Activating Transcription Factor 4 (ATF4)
Zdroj: International Journal of Molecular Sciences
Volume 19
Issue 12
International Journal of Molecular Sciences, Vol 19, Iss 12, p 4032 (2018)
ISSN: 1422-0067
Popis: A variety of cellular stresses lead to global translation attenuation due to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2), which decreases the availability of the eIF2-GTP-Met-tRNAi ternary complex. However, a subset of mRNAs continues to be translated by non-canonical mechanisms under these conditions. In fact, although translation initiation of activating transcription factor 4 (ATF4) is normally repressed by an upstream open reading frame (uORF), a decreased availability of ternary complex leads to increased translation of the main ATF4-coding ORF. We show here that siRNA-mediated depletion of eIF5B&mdash
which can substitute for eIF2 in delivering Met-tRNAi&mdash
leads to increased levels of ATF4 protein in mammalian cells. This de-repression is not due to phosphorylation of eIF2&alpha
under conditions of eIF5B depletion. Although eIF5B depletion leads to a modest increase in the steady-state levels of ATF4 mRNA, we show by polysome profiling that the depletion of eIF5B enhances ATF4 expression primarily at the level of translation. Moreover, eIF5B silencing increases the expression of an ATF4-luciferase translational reporter by a mechanism requiring the repressive uORF2. Further experiments suggest that eIF5B cooperates with eIF1A and eIF5, but not eIF2A, to facilitate the uORF2-mediated repression of ATF4 translation.
Databáze: OpenAIRE
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