A New Paradigm for Translational Control: Inhibition via 5-3 mRNA Tethering by Bicoid and the eIF4E Cognate 4EHP

Translational control is a key genetic regulatory mechanism implicated in regulation of cell and organismal growth and early embryonic development. Initiation at the mRNA 5ʹ cap structure recognition step is frequently targeted by translational control mechanisms. In the Drosophila embryo, cap-dependent translation of the uniformly distributed caudal (cad) mRNA is inhibited in the anterior by Bicoid (Bcd) to create an asymmetric distribution of Cad protein. Here, we show that d4EHP, an eIF4E-related cap binding protein, specifically interacts with Bcd to suppress cad translation. Translational inhibition depends on the Bcd binding region (BBR) present in the cad 3ʹ untranslated region. Thus, simultaneous interactions of d4EHP with the cap structure and of Bcd with BBR renders cad mRNA translationally inactive. This example of cap-dependent translational control that is not mediated by canonical eIF4E defines a new paradigm for translational inhibition involving tethering of the mRNA 5ʹ and 3ʹ ends.