Molecular mechanisms of translational control

Abstract

Translational regulation can be global or mRNA specific, and most examples of translational regulation that have been described so far affect the rate-limiting initiation step. Global control of translation is frequently exerted by regulating the phosphorylation or availability of initiation factors. Two of the most well-known examples are the regulation of eukaryotic initiation factor (eIF)4E availability by 4E-binding proteins (4E-BPs), and the modulation of the levels of active ternary complex by eIF2α phosphorylation. mRNA-specific translational control is driven by RNA sequences and/or structures that are commonly located in the untranslated regions of the transcript. These features are usually recognized by regulatory proteins or micro RNAs (miRNAs). Quasi-circularization of mRNAs can be mediated by the cap structure and the poly(A) tail via the eIF4E–eIF4G–polyA-binding-protein (PABP) interaction. Such interactions between the 5′ and the 3′ ends of mRNAs could provide a spatial framework for the action of regulatory factors that bind to the 3′ untranslated region (UTR). However, other forms of 5′–3′-end interactions are likely to occur as well. Many regulatory proteins target the stable association of the small ribosomal subunit with the mRNA. These factors function by steric hindrance (for example, iron-regulatory protein; IRP), by interfering with the eIF4F complex (for example, Maskin, Bicoid, Cup) or by as-yet-unknown, distinct mechanisms to control translation initiation (sex-lethal; SXL). Other regulatory molecules modulate the joining of the large ribosomal subunit (hnRNP K and E1) or, potentially, post-initiation translation steps (miRNAs). General translation factors can regulate the expression of specific mRNAs. An illustrative example is the stimulation of translation of the mRNA that encodes the GCN4 transcriptional activator by eIF2α phosphorylation.