Trading translation with RNA-binding proteins

Abstract

RNA-binding proteins regulate every aspect of RNA metabolism, including pre-mRNA splicing, mRNA trafficking, stability, and translation. This review summarizes the available information on molecular mechanisms of translational repression by RNA-binding proteins. By using a specific set of well-defined examples, we also describe how regulation can be reversed.

FIGURE 1.

Translation initiation and its regulation by RNA-binding proteins. The translation initiation pathway and factors are depicted in gray (see text for details). The term eIF has been omitted for simplicity. Only the translation factors mentioned in this review are shown. The regulators and the steps that they inhibit are shown in red. Cap-dependent mechanisms of translational control target the association of eIF4E with the cap structure (yellow oval), the interaction of eIF4E with eIF4G, the interaction of eIF4G with eIF3, or sterically hinder 43S ribosomal recruitment. Cap-independent mechanisms can block 43S recruitment, ribosomal scanning, or 60S subunit joining.

FIGURE 2.

Reversion of translational repression. mRNAs in their repressed and activated states are shown, as well as the signals leading to activation. (A) Translational activation by remodeling of the repressed RNP. In immature Xenopus oocytes, CPEB recruits a repressor complex composed of the 4E-BP Maskin and the deadenylase PARN. Upon progesterone stimulation, phosphorylation of CPEB allows the dissociation of PARN and the productive polyadenylation by a complex composed of symplekin, CPSF and Gld2. The poly(A) tail then recruits PABP, which binds to eIF4G, resulting in Maskin displacement. Maskin phosphorylation also contributes to de-repression. For simplicity, the polyadenylation complex is depicted bound to the mRNA only in maturing oocytes (see text for details). (B) Removal of the repressor by phosphorylation. hnRNP K is phosphorylated by c-Src, leading to its dissociation from the DICE element in LOX 3′ UTR. Methylation (Me) of hnRNP K inhibits its association with c-Src. (C) Binding of IRP to the small molecule cofactor [4Fe–4S] prevents its interaction with the IRE element in the 5′ UTR of ferritin mRNA.