5 years ago

Cap-binding protein 4EHP effects translation silencing by microRNAs [Biochemistry]

Cap-binding protein 4EHP effects translation silencing by microRNAs [Biochemistry]
Idit A. Gelbart, Tommy Alain, Clement Chapat, Edna Matta–Camacho, Christos G. Gkogkas, Noam Stern–Ginossar, Thomas F. Duchaine, Geoffrey G. Hesketh, Marc R. Fabian, Anne–Claude Gingras, Nahum Sonenberg, Jan Attig, Seyed Mehdi Jafarneȷad

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.

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