Cap-binding protein 4EHP effects translation silencing by microRNAs

MicroRNAs (miRNAs) play critical roles in a broad variety of biological processes by inhibiting translation initiation and by destabilizing target mRNAs. The CCR4–NOT complex effects miRNA-mediated silencing, at least in part through interactions with 4E-T (eIF4E transporter) protein, but the precis...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 21; pp. 5425 - 5430
Main Authors Chapat, Clément, Jafarnejad, Seyed Mehdi, Matta-Camacho, Edna, Hesketh, Geoffrey G., Gelbart, Idit A., Attig, Jan, Gkogkas, Christos G., Alain, Tommy, Stern-Ginossar, Noam, Fabian, Marc R., Gingras, Anne-Claude, Duchaine, Thomas F., Sonenberg, Nahum
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 23.05.2017
Subjects
Binding sites
Biological activity
Biological Sciences
Cap-binding protein
HEK293 Cells
HeLa Cells
Homology
Humans
Initiation factor eIF-4E
Machinery and equipment
MicroRNAs - metabolism
miRNA
mRNA
Nucleocytoplasmic Transport Proteins - metabolism
Protein transport
Proteins
Ribonucleic acid
RNA
RNA Cap-Binding Proteins - metabolism
RNA Interference
RNA-Induced Silencing Complex - metabolism
Translation initiation
4E-T
4EHP
microRNA
CCR4–NOT
mRNA translation
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Summary:MicroRNAs (miRNAs) play critical roles in a broad variety of biological processes by inhibiting translation initiation and by destabilizing target mRNAs. The CCR4–NOT complex effects miRNA-mediated silencing, at least in part through interactions with 4E-T (eIF4E transporter) protein, but the precise mechanism is unknown. Here we show that the cap-binding eIF4E-homologous protein 4EHP is an integral component of the miRNA-mediated silencing machinery. We demonstrate that the cap-binding activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4–NOT complex. Our results show that 4EHP competes with eIF4E for binding to 4E-T, and this interaction increases the affinity of 4EHP for the cap. We propose a model wherein the 4E-T/4EHP interaction engenders a closed-loopmRNA conformation that blocks translational initiation of miRNA targets.
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Contributed by Nahum Sonenberg, April 11, 2017 (sent for review January 30, 2017; reviewed by Reuven Agami and Nancy Standart)
1C.C. and S.M.J. contributed equally to this work.
Reviewers: R.A., The Netherlands Cancer Institute; and N.S., University of Cambridge.
Author contributions: C.C. and S.M.J. designed research; C.C., S.M.J., E.M.-C., G.G.H., and T.A. performed research; C.C., S.M.J., E.M.-C., G.G.H., J.A., C.G.G., M.R.F., and A.-C.G. contributed new reagents/analytic tools; C.C., S.M.J., E.M.-C., G.G.H., I.A.G., J.A., N.S.-G., A.-C.G., and N.S. analyzed data; and C.C., S.M.J., T.F.D., and N.S. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1701488114