Translation termination efficiency modulates ATF4 response by regulating ATF4 mRNA translation at 5' short ORFs.
The activating transcription factor 4 (ATF4) promotes transcriptional upregulation of specific target genes in response to cellular stress. ATF4 expression is regulated at the translational level by two short open reading frames (uORFs) in its 5'-untranslated region (5'-UTR). Here, we describe a mechanism regulating ATF4 expression in translation termination-deficient human cells. Using microarray analysis of total RNA and polysome-associated mRNAs, we show that depletion of the eucaryotic release factor 3a (eRF3a) induces upregulation of ATF4 and of ATF4 target genes. We show that eRF3a depletion modifies ATF4 translational control at regulatory uORFs increasing ATF4 ORF translation. Finally, we show that the increase of REDD1 expression, one of the upregulated targets of ATF4, is responsible for the mTOR pathway inhibition in eRF3a-depleted cells. Our results shed light on the molecular mechanisms connecting eRF3a depletion to mammalian target of rapamycin (mTOR) pathway inhibition and give an example of ATF4 activation that bypasses the signal transduction cascade leading to the phosphorylation of eIF2α. We propose that in mammals, in which the 5'-UTR regulatory elements of ATF4 mRNA are strictly conserved, variations in translation termination efficiency allow the modulation of the ATF4 response.
UPMC Univ Paris 06, CNRS-FRE 3402, Biologie de l'ARN, 9 quai Saint Bernard, 75005 Paris, France.
Hayet
H
Ait Ghezala
Béatrice
B
Jolles
Samia
S
Salhi
Katia
K
Castrillo
Wassila
W
Carpentier
Nicolas
N
Cagnard
Alain
A
Bruhat
Pierre
P
Fafournoux
Olivier
O
Jean-Jean
D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D010443:Peptide Chain Termination, Translational; D010454:Peptide Termination Factors / Q000235:genetics / Q000502:physiology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome
C497109:ATF4 protein, human; C469991:DDIT4 protein, human; D010454:Peptide Termination Factors; D012333:RNA, Messenger; D014157:Transcription Factors; C087971:peptide-chain-release factor 3; D051701:Activating Transcription Factor 4; D058570:TOR Serine-Threonine Kinases