MicroRNA silencing through RISC recruitment of eIF6.
MicroRNAs (miRNAs) are a class of small RNAs that act post-transcriptionally to regulate messenger RNA stability and translation. To elucidate how miRNAs mediate their repressive effects, we performed biochemical and functional assays to identify new factors in the miRNA pathway. Here we show that human RISC (RNA-induced silencing complex) associates with a multiprotein complex containing MOV10--which is the homologue of Drosophila translational repressor Armitage--and proteins of the 60S ribosome subunit. Notably, this complex contains the anti-association factor eIF6 (also called ITGB4BP or p27BBP), a ribosome inhibitory protein known to prevent productive assembly of the 80S ribosome. Depletion of eIF6 in human cells specifically abrogates miRNA-mediated regulation of target protein and mRNA levels. Similarly, depletion of eIF6 in Caenorhabditis elegans diminishes lin-4 miRNA-mediated repression of the endogenous LIN-14 and LIN-28 target protein and mRNA levels. These results uncover an evolutionarily conserved function of the ribosome anti-association factor eIF6 in miRNA-mediated post-transcriptional silencing.
Chendrimada
Thimmaiah P
TP
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Finn
Kenneth J
KJ
Ji
Xinjun
X
Baillat
David
D
Gregory
Richard I
RI
Liebhaber
Stephen A
SA
Pasquinelli
Amy E
AE
Shiekhattar
Ramin
R
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D034622:RNA Interference; D018510:RNA, Helminth / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D034743:RNA-Induced Silencing Complex / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D000099253:Trans-Activation Responsive RNA-Binding Protein
D029742:Caenorhabditis elegans Proteins; D039642:Eukaryotic Initiation Factors; D035683:MicroRNAs; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D018510:RNA, Helminth; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D034743:RNA-Induced Silencing Complex; D012097:Repressor Proteins; D000099253:Trans-Activation Responsive RNA-Binding Protein; C109284:EIF6 protein, human; C102669:LIN-14 protein, C elegans; C452195:LIN-28 protein, C elegans; C520674:eif-6 protein, C elegans; C452194:lin-4 microRNA, C elegans; C487931:mirnlet7 microRNA, human