MicroRNAs Trigger Dissociation of eIF4AI and eIF4AII from Target mRNAs in Humans

In animals, key functions of microRNA-induced silencing complex (miRISC) are translational repression and deadenylation followed by mRNA decay. While miRISC represses translation initiation, it is poorly understood how miRISC exerts this function. Here we assessed the effect of miRISC on synergistic...

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Bibliographic Details
Published in:Molecular cell 2014-10, Vol.56 (1), p.79-89
Main Authors: Fukao, Akira, Mishima, Yuichiro, Takizawa, Naoki, Oka, Shigenori, Imataka, Hiroaki, Pelletier, Jerry, Sonenberg, Nahum, Thoma, Christian, Fujiwara, Toshinobu
Format: Article
Language:English
Subjects:
Eukaryotic Initiation Factor-4A - antagonists & inhibitors
Eukaryotic Initiation Factor-4A - genetics
Eukaryotic Initiation Factor-4A - metabolism
HEK293 Cells
Humans
MicroRNAs - physiology
Models, Genetic
RNA, Messenger - metabolism
RNA-Induced Silencing Complex - physiology
Transcription Initiation, Genetic
Triterpenes - pharmacology
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Summary:In animals, key functions of microRNA-induced silencing complex (miRISC) are translational repression and deadenylation followed by mRNA decay. While miRISC represses translation initiation, it is poorly understood how miRISC exerts this function. Here we assessed the effect of miRISC on synergistic recruitment of translation initiation factors to target mRNAs by using direct biochemical assays. We show that miRISC promotes eIF4AI and eIF4AII release from target mRNAs prior to dissociation of eIF4E and eIF4G in a deadenylation-independent manner. Strikingly, miRISC-induced release of eIF4AI and eIF4AII from target mRNAs and miRISC-induced inhibition of cap-dependent translation can both be counteracted by the RNA-binding protein HuD via a direct interaction of HuD with eIF4A. Furthermore, the pharmacological eIF4A inhibitor silvestrol, which locks eIF4A on mRNAs, conferred resistance to miRNA-mediated translational repression. In summary, we propose that both eIF4AI and eIF4AII are functionally important targets in miRISC-mediated translation control. [Display omitted] •miRISC induces dissociation of both eIF4AI and eIF4AII from mRNA in human cells•The RNA-binding protein HuD attenuates the miRISC-induced translational repression•Silvestrol inhibits microRNA-mediated repression in vitro and in cells MicroRNAs induce translational repression and deadenylation followed by mRNA decay. Fukao et al. show that miRNAs in human cells cause deadenylation-independent dissociation of eIF4AI and eIF4AII from mRNA prior to dissociation of eIF4E and eIF4G.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2014.09.005