2. Academic Validation
  3. Cap-binding protein 4EHP effects translation silencing by microRNAs

Cap-binding protein 4EHP effects translation silencing by microRNAs

  • Proc Natl Acad Sci U S A. 2017 May 23;114(21):5425-5430. doi: 10.1073/pnas.1701488114.
Clément Chapat 1 2,  Seyed Mehdi Jafarnejad 1 2,  Edna Matta-Camacho 1 2,  Geoffrey G Hesketh 3,  Idit A Gelbart 4,  Jan Attig 5,  Christos G Gkogkas 6,  Tommy Alain 7,  Noam Stern-Ginossar 4,  Marc R Fabian 8,  Anne-Claude Gingras 3 9,  Thomas F Duchaine 10 2,  Nahum Sonenberg 10 2
Affiliations

Affiliations

  • 1 Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
  • 2 Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
  • 3 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.
  • 4 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 5 The Francis Crick Institute, London NW1 1AT, United Kingdom.
  • 6 Patrick Wild Centre, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
  • 7 Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • 8 Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3A 1A3, Canada.
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.
  • 10 Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada; nahum.sonenberg@mcgill.ca thomas.duchaine@mcgill.ca.
PMID: 28487484 DOI: 10.1073/pnas.1701488114
Abstract

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-loop mRNA conformation that blocks translational initiation of miRNA targets.

Keywords

4E-T; 4EHP; CCR4–NOT; mRNA translation; microRNA.

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