Non-AUG translation initiation in mammals

Abstract

Recent proteogenomic studies revealed extensive translation outside of annotated protein coding regions, such as non-coding RNAs and untranslated regions of mRNAs. This non-canonical translation is largely due to start codon plurality within the same RNA. This plurality is often due to the failure of some scanning ribosomes to recognize potential start codons leading to initiation downstream-a process termed leaky scanning. Codons other than AUG (non-AUG) are particularly leaky due to their inefficiency. Here we discuss our current understanding of non-AUG initiation. We argue for a near-ubiquitous role of non-AUG initiation in shaping the dynamic composition of mammalian proteomes.

Fig. 1

Utilization of non-AUG initiation. Variation of non-AUG initiation with known examples. Non-AUG codons are denoted with NUG (they may differ from AUG in the second and third position)

Fig. 2

Ribo-seq profiles of MYC (example of PANTS: AUG and extended CUG proteoforms) and EIF4G2 (example of exclusive non-AUG initiation). Reading frames are colored in red, green, and blue; AUGs (white bars) and stop codons (black bars) are shown within the bottom frame color bars. The asterisk (*) in EIF4G2 represents upstream non-AUG initiation at AUU codon; a downstream out-of-frame short AUG ORF is depicted by a blue arrow; the main ORF (CDS) is shown as a gray bar. In the MYC profile, AUG and CUG proteoforms (main ORFs) are shown as gray bars, and AUG uORFs are shown as red arrows

Fig. 3

Global and mRNA-specific regulation of non-AUG translation. A Global regulation of non-AUG initiation by eIF1/BZW/eIF5 “stringency” factors and the regulatory circuit that ensures their levels are tightly controlled. B Downstream secondary structures and/or RNA binding protein sites render mRNA translation sensitive to specific RNA helicase action. C Stimulatory effect on non-AUG initiation by a preceding slowly elongating or paused 80S ribosome