title: MicroRNAs trigger dissociation of eIF4AI and eIF4AII from target mRNAs in humans.
abstract: 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.
authors.affiliation: Laboratory of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fukao
authors.affiliation: Institute of Molecular and Cellular Biosciences, Department of Medical Genome Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Institute of Microbial Chemistry, Laboratory of Basic Biology, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takizawa
authors.affiliation: Pharma Medical Division, Life & Healthcare Products Department, Nagase & Co., Ltd., 2-2-3 Murotani, Nishi-ku, Kobe, Hyogo 651-2241, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Oka
authors.affiliation: Department of Materials Science and Chemistry, Graduate School of Engineering, University of Hyogo, Himeji 671-2280, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Imataka
authors.affiliation: Department of Biochemistry, Department of Oncology, and The Rosalind and Morris Goodman Cancer Research Center and McGill Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Biochemistry, Department of Oncology, and The Rosalind and Morris Goodman Cancer Research Center and McGill Cancer Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: Department of Medicine II, University Hospital of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thoma
authors.affiliation: Laboratory of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan. Electronic address: tosinobu@phar.nagoya-cu.ac.jp.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D008957:Models, Genetic; D012333:RNA, Messenger / Q000378:metabolism*; D034743:RNA-Induced Silencing Complex / Q000502:physiology; D061785:Transcription Initiation, Genetic; D014315:Triterpenes / Q000494:pharmacology; D001572:Benzofurans
chemical_list: D039601:Eukaryotic Initiation Factor-4A; D035683:MicroRNAs; D012333:RNA, Messenger; D034743:RNA-Induced Silencing Complex; D014315:Triterpenes; C489897:silvestrol; D001572:Benzofurans