MicroRNA silencing through RISC recruitment of eIF6

Thimmaiah P. Chendrimada; Kenneth J. Finn; Xinjun Ji; David Baillat; Richard I. Gregory; Stephen A. Liebhaber; Amy E. Pasquinelli; Ramin Shiekhattar

doi:10.1038/nature05841

MicroRNA silencing through RISC recruitment of eIF6

Thimmaiah P. Chendrimada, Kenneth J. Finn, Xinjun Ji, David Baillat, Richard I. Gregory, Stephen A. Liebhaber, Amy E. Pasquinelli, Ramin Shiekhattar

Research output: Contribution to journal › Article › peer-review

360 Scopus citations

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.

Original language	English (US)
Pages (from-to)	823-828
Number of pages	6
Journal	Nature
Volume	447
Issue number	7146
DOIs	https://doi.org/10.1038/nature05841
State	Published - Jun 14 2007
Externally published	Yes

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@article{2d0de22a47614c58bc6f8b6af097bb42,

title = "MicroRNA silencing through RISC recruitment of eIF6",

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.",

author = "Chendrimada, {Thimmaiah P.} and Finn, {Kenneth J.} and Xinjun Ji and David Baillat and Gregory, {Richard I.} and Liebhaber, {Stephen A.} and Pasquinelli, {Amy E.} and Ramin Shiekhattar",

note = "Funding Information: Acknowledgements We thank Z. Mourelatos for providing the firefly luciferase plasmids containing let-7b binding sites; J. Belasco for Luc-lin28 (firefly luciferase reporter fused to the 2.7-kb 39 UTR of human LIN28) and its mutants; G. Ruvkun and E. Moss for LIN-14 and LIN-28 antibodies, respectively; and J. Bracht, M. G. Lee, S. Bagga and G. Harris for technical assistance. We also thank T. Beer of the Wistar Proteomics Facility for expertise in the microcapillary HPLC/mass spectrometry. This work was supported by NIH (A.E.P., R.S., S.A.L.), the Searle and V Foundations (AEP), the Mathers Foundation (RS) and a Cooley{\textquoteright}s Anemia Foundation Fellowship to X.J.",

year = "2007",

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doi = "10.1038/nature05841",

language = "English (US)",

volume = "447",

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journal = "Nature",

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T1 - MicroRNA silencing through RISC recruitment of eIF6

AU - Chendrimada, Thimmaiah P.

AU - Finn, Kenneth J.

AU - Ji, Xinjun

AU - Baillat, David

AU - Gregory, Richard I.

AU - Liebhaber, Stephen A.

AU - Pasquinelli, Amy E.

AU - Shiekhattar, Ramin

N1 - Funding Information: Acknowledgements We thank Z. Mourelatos for providing the firefly luciferase plasmids containing let-7b binding sites; J. Belasco for Luc-lin28 (firefly luciferase reporter fused to the 2.7-kb 39 UTR of human LIN28) and its mutants; G. Ruvkun and E. Moss for LIN-14 and LIN-28 antibodies, respectively; and J. Bracht, M. G. Lee, S. Bagga and G. Harris for technical assistance. We also thank T. Beer of the Wistar Proteomics Facility for expertise in the microcapillary HPLC/mass spectrometry. This work was supported by NIH (A.E.P., R.S., S.A.L.), the Searle and V Foundations (AEP), the Mathers Foundation (RS) and a Cooley’s Anemia Foundation Fellowship to X.J.

PY - 2007/6/14

Y1 - 2007/6/14

N2 - 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.

AB - 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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DO - 10.1038/nature05841

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VL - 447

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JO - Nature

JF - Nature

IS - 7146

ER -

MicroRNA silencing through RISC recruitment of eIF6

Abstract

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