Translational Control by a Small RNA: Dendritic BC1 RNA Targets the Eukaryotic Initiation Factor 4A Helicase Mechanism

Abstract

Translational repressors, increasing evidence suggests, participate in the regulation of protein synthesis at the synapse, thus providing a basis for the long-term plastic modulation of synaptic strength. Dendritic BC1 RNA is a non-protein-coding RNA that represses translation at the level of initiation. However, the molecular mechanism of BC1 repression has remained unknown. Here we identify the catalytic activity of eukaryotic initiation factor 4A (eIF4A), an ATP-dependent RNA helicase, as a target of BC1-mediated translational control. BC1 RNA specifically blocks the RNA duplex unwinding activity of eIF4A but, at the same time, stimulates its ATPase activity. BC200 RNA, the primate-specific BC1 counterpart, targets eIF4A activity in identical fashion, as a result decoupling ATP hydrolysis from RNA duplex unwinding. In vivo, BC1 RNA represses translation of a reporter mRNA with 5′ secondary structure. The eIF4A mechanism places BC RNAs in a central position to modulate protein synthesis in neurons.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank A. Komar and W. Merrick for advice on helicase assays, M. Dattilo for HEK293 cells, T. Preiss for pOT.CAT plasmids, and members of the Hellen, Pestova, and Tiedge labs for advice and discussion. Statistical consultation was provided by J. Weedon (SUNY Brooklyn Scientific Computing Center).

This work was supported in part by National Institutes of Health grants AI51340 (C.U.T.H.), GM059660 (T.V.P.), and NS046769 (H.T.).