Translational control of ERK signaling through miRNA/4EHP-directed silencing

Seyed Mehdi Jafarnejad, Clément Chapat, Edna Matta-Camacho, Idit Anna Gelbart, Geoffrey G Hesketh, Meztli Arguello, Aitor Garzia, Sung-Hoon Kim, Jan Attig, Maayan Shapiro, Masahiro Morita, Arkady Khoutorsky, Tommy Alain, G Gkogkas Christos, Noam Stern-Ginossar, Thomas Tuschl, Anne-Claude Gingras, Thomas F Duchaine, Nahum Sonenberg

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Abstract

MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. This promotes ERK1/2 phosphorylation, resulting in augmented cell growth and reduced apoptosis. Our findings thus empirically define the integral role of translational repression in miRNA-induced gene silencing and reveal a critical function for this process in the control of the ERK signaling cascade in mammalian cells.
Original languageEnglish
Article numbere35034
Number of pages18
JournaleLife
Volume7
DOIs
Publication statusPublished - 20 Feb 2018

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    Jafarnejad, S. M., Chapat, C., Matta-Camacho, E., Gelbart, I. A., Hesketh, G. G., Arguello, M., Garzia, A., Kim, S-H., Attig, J., Shapiro, M., Morita, M., Khoutorsky, A., Alain, T., Christos, G. G., Stern-Ginossar, N., Tuschl, T., Gingras, A-C., Duchaine, T. F., & Sonenberg, N. (2018). Translational control of ERK signaling through miRNA/4EHP-directed silencing. eLife, 7, [e35034]. https://doi.org/10.7554/eLife.35034