1. The Wistar Institute, 3601 Spruce Street, and
2. Department of Genetics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
3. Department of Biology, University of California, San Diego, La Jolla, California 92093-0349, USA
4. Present address: Center de Regulacio Genomica Dr. Aiguader, 88 08003 Barcelona, Spain.

Correspondence to: Amy E. Pasquinelli³Ramin Shiekhattar^1,4 Correspondence and requests for materials should be addressed to R.S. (Email: ramin.shiekhattar@crg.es) or A.E.P. (Email: apasquin@ucsd.edu).

Abstract

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.

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