Fig. 4.

The roles of uORFs in translational control. In addition to reinitiation (Fig. 2) uORFs have been characterised to perform a number of different roles. (A) The nucleotide sequence can have a predominant role on uORF translatability, for instance by encoding for rare codons that cause the ribosome to stall (methionine synthase) or the potential involvement of such sequences in secondary structure or RNA motifs (UCP2). The peptide product of uORFs can have cis regulatory functions, for instance causing the stalling of ribosomes (AdoMetDC and CHOP) (B), or by the trans repression of the mORF (AS, β2 adrenergic receptor and vasopressin V1B receptor) (C). (D) Bypass of an inhibitory uORF has been observed under stress conditions and is dependent on eIF2α phosphorylation. An interesting possibility for how this may occur is the loading of the 40S without an eIF2-TC which it acquires as it scans (C/EBP α and β, CHOP, GADD34, protein kinase C isoform η). (E) Interactions that involve both uORFs and IRES elements within 5′UTRs can cause expression of the mORF (Cat-1) or repression of particular splice variants (VEGF-A). (F) Approximately 35–50% of uORF containing transcripts undergo selective degradation by NMD (e.g. ATF4, CHOP and IFDR1).