Translational control by 5'-untranslated regions of eukaryotic mRNAs

Abstract

The eukaryotic 5' untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5' upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5'UTR, including particular sequence motifs. We also discuss translational control via phosphorylation of eukaryotic initiation factor 2, which is implicated in learning and memory, neurodegenerative diseases, and cancer.

Fig. 1.. The scanning mechanism of translation initiation.

The simpler 5-subunit version of budding yeast eIF3 is depicted. See text for details.

Fig. 2.. Mechanisms of translational control by short uORFs.

(i) 43S PICs scanning from the mRNA 5’end translate the uORF (as 80S ribosomes) and free subunits dissociate from the mRNA following termination, preventing translation of the main ORF (mORF). (ii) 80S ribosomes are stalled during elongation or termination by the uORF-encoded attenuator peptide and impose a barrier to scanning 43S PICs that leaky-scan the uORF start codon, preventing translation of the mORF. Stalling is modulated by small molecules (see text).

Fig 3.. Different gene architectures conferring translational control by short uORFs.

i) 1. Scanning PICs that translate the uORF fail to reinitiate at the mORF, as depicted in Fig. 2. 2. A fraction of scanning PICs leaky-scan the uORF start codon, enhanced by its suboptimal context, and initiate at the mORF instead. Leaky-scanning can be induced by elevated eIF5 levels for the eIF5 structural gene (4), by eIF2(αP), eg. for GADD34 (36) and IFRD (35); and by polyamines for AMD1 (encoding SAMDC) and AZIN1 (34). ii) 1. Scanning ribosomes initiate translation of a short uORF whose translation does not preclude reinitiation. 2. Resumed scanning followed by quick reacquisition of TC enables translation of an inhibitory downstream uORF that precludes further reinitiation. 3. Slow reacquisition of TC at reduced TC concentrations evoked by eIF2(αP) allows reinitiation further downstream at the mORF. Examples include GCN4 (37) and ATF4 (38, 39). iii) 1. Scanning ribosomes initiate translation of a short uORF permissive for reinitiation. 2. Ribosomes that leaky-scan the first uORF translate a second inhibitory uORF that precludes reinitiation. 3. Ribosomes that translate the first uORF resume scanning and reacquire TC only after bypassing the second uORF, avoiding its inhibitory effect. Exemplified by polyamine regulation of SAMDC synthesis in plants (34). iv) 1. Ribosomes initiate at an upstream start codon in-frame with the mORF and bypass an inhibitory uORF during elongation while producing protein isoform “a” with specific properties. 2. Scanning subunits bypass the in-frame start site, owing to its suboptimal context, and initiate downstream at the uORF. 3. Re-scanning followed by quick reacquisition of TC leads to reinitiation at a proximal start codon to produce protein isoform “b”. 4. Slow re-acquisition of TC allows initiation further downstream producing the shortest isoform “c”, with activities opposite those of “a” and “b”. Examples include C/EBP-α and C/EBP-β (49).