Translation termination efficiency modulates ATF4 response by regulating ATF4 mRNA translation at 5' short ORFs.
Translation termination efficiency modulates ATF4 response by regulating ATF4 mRNA translation at 5' short ORFs.
复制标题
DOI：
10.1093/nar/gks762
复制
发表时间：
2012-10
影响因子：
14.9
通讯作者：
Jean-Jean O
中科院分区：
文献类型：
--
作者：
Ait Ghezala H;Jolles B;Salhi S;Castrillo K;Carpentier W;Cagnard N;Bruhat A;Fafournoux P;Jean-Jean O
激活转录因子4(ATF4)促进特定靶基因的转录上调，以响应细胞应激。ATF4的表达受其5‘-非翻译区的两个短开放阅读框(UORF)在翻译水平上的调控。在这里，我们描述了一种在翻译终止缺陷的人类细胞中调节ATF4表达的机制。利用总RNA和多聚体相关mRNAs的微阵列分析，我们发现真核释放因子3a(ERF3a)的缺失会导致ATF4和ATF4靶基因的上调。我们发现eRF3a缺失在调节uORF增加ATF4 ORF翻译时改变了ATF4翻译控制。最后，我们证明，作为ATF4上调靶点之一的Redd1表达的增加，是eRF3a缺失细胞mTOR通路抑制的原因之一。我们的结果揭示了eRF3a缺失与哺乳动物雷帕霉素途径抑制靶点之间的分子机制，并提供了一个绕过导致eIF2α磷酸化的信号转导级联的ATF4激活的例子。我们认为，在哺乳动物中，ATF4 mRNA的5‘-UTR调控元件是严格保守的，翻译终止效率的变化允许调节ATF4的反应。
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.
登录
查看更多内容
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
9.2
作者：
Deng, J;Harding, HP;Sonenberg, N
通讯作者：
Sonenberg, N
影响因子：
11.4
作者：
Ivanov, Pavel V.;Gehring, Niels H.;Kulozik, Andreas E.
通讯作者：
Kulozik, Andreas E.
影响因子：
4.5
作者：
Chauvin, Celine;Jean-Jean, Olivier
通讯作者：
Jean-Jean, Olivier
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y