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

doi:10.7554/eLife.35034

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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39 Scopus citations

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 language	English (US)
Article number	e35034
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.35034
State	Published - Feb 7 2018

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.35034

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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, Article e35034. https://doi.org/10.7554/eLife.35034

Jafarnejad, SM, Chapat, C, Matta-Camacho, E, Gelbart, IA, Hesketh, GG, Arguello, M, Garzia, A, Kim, SH, Attig, J, Shapiro, M, Morita, M, Khoutorsky, A, Alain, T, Christos, GG, Stern-Ginossar, N, Tuschl, T, Gingras, AC, Duchaine, TF & Sonenberg, N 2018, 'Translational control of ERK signaling through miRNA/4EHP-directed silencing', eLife, vol. 7, e35034. https://doi.org/10.7554/eLife.35034

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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.",

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AU - Hesketh, Geoffrey G.

AU - Arguello, Meztli

AU - Garzia, Aitor

AU - Kim, Sung Hoon

AU - Attig, Jan

AU - Shapiro, Maayan

AU - Morita, Masahiro

AU - Khoutorsky, Arkady

AU - Alain, Tommy

AU - Christos, G. Gkogkas

AU - Stern-Ginossar, Noam

AU - Tuschl, Thomas

AU - Gingras, Anne Claude

AU - Duchaine, Thomas F.

AU - Sonenberg, Nahum

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

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