Figure 4. Translational Control via the 3′ UTR.

(A) Models for cap-dependent translational repression by soluble or tethered eIF4E-binding proteins. Cap-dependent initiation requires interaction of eIF4E with the mRNA 5′ cap structure, which forms the eIF4F complex together with RNA helicase eIF4A and eIF4G. By binding to both eIF4E and PABP, eIF4G mediates circularization of mRNA. A general mechanism of translational repression involves the 4E-binding proteins (4E-BPs), which compete with eIF4G for interaction with eIF4E. Other repression mechanisms are more mRNA specific. Translation of mRNAs containing a cytoplasmic polyadenylation element (CPE) is repressed by displacement of eIF4G by Maskin/4E-T, recruited to the mRNA by CPE-binding protein (CPEB). The latter model works for specific mRNAs using different modules. Translation of Drosophila oskar mRNA is inhibited by tethering eIF4E to the Bruno response element (BRE) via Bruno and Cup. A variation on the theme is presented by Bicoid, which inhibits Drosophila caudal mRNA translation by binding simultaneously to the 3′UTR Bicoid-binding region (BBR) and the eIF4E-homologous protein 4E-HP (adapted from Sonenberg and Hinnebusch, 2007).

(B) Translational repression of ceruloplasmin mRNA upon interferon-γ treatment involves formation of the GAIT complex from Glu-Pro-tRNA synthetase, NS-associated protein 1, GAPDH, and 60S ribosomal protein L13a (released by phosphorylation from the 60S subunit). The complex binds to the GAIT element in the 3′UTR and blocks interaction of eIF4G with eIF3 in the 43S PIC to prevent 48S PIC assembly on ceruloplasmin mRNA (adapted from Kapasi et al., 2007).

(C) Dual repression of male-specific lethal 2 (msl-2) mRNA translation by sex lethal (SXL) protein. Bound to the 3′UTR, SXL recruits UNR (upstream of N-ras) protein to block 43S PIC binding to the 5′ end of the mRNA. SXL also targets scanning ribosomes in the 5′UTR for a backup repression mechanism (figure kindly provided by Matthias Hentze and colleagues).