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
  • 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; [email protected] [email protected].
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.