Competition between translation initiation factor eIF5 and its mimic protein 5MP determines non-AUG initiation rate genome-wide

Nucleic Acids Res. 2017 Nov 16;45(20):11941-11953. doi: 10.1093/nar/gkx808.


In the human genome, translation initiation from non-AUG codons plays an important role in various gene regulation programs. However, mechanisms regulating the non-AUG initiation rate remain poorly understood. Here, we show that the non-AUG initiation rate is nearly consistent under a fixed nucleotide context in various human and insect cells. Yet, it ranges from <1% to nearly 100% compared to AUG translation, depending on surrounding sequences, including Kozak, and possibly additional nucleotide contexts. Mechanistically, this range of non-AUG initiation is controlled in part, by the eIF5-mimic protein (5MP). 5MP represses non-AUG translation by competing with eIF5 for the Met-tRNAi-binding factor eIF2. Consistently, eIF5 increases, whereas 5MP decreases translation of NAT1/EIF4G2/DAP5, whose sole start codon is GUG. By modulating eIF5 and 5MP1 expression in combination with ribosome profiling we identified a handful of previously unknown non-AUG initiation sites, some of which serve as the exclusive start codons. If the initiation rate for these codons is low, then an AUG-initiated downstream ORF prevents the generation of shorter, AUG-initiated isoforms. We propose that the homeostasis of the non-AUG translatome is maintained through balanced expression of eIF5 and 5MP.

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Line
  • Cell Line, Tumor
  • Codon, Initiator / genetics*
  • Codon, Initiator / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factor-5 / genetics*
  • Eukaryotic Initiation Factor-5 / metabolism
  • Gene Expression Regulation
  • Genome, Human*
  • HEK293 Cells
  • Homeostasis / genetics
  • Humans
  • Protein Binding
  • Protein Biosynthesis / genetics
  • Ribosomes / genetics
  • Ribosomes / metabolism


  • BZW2 protein, human
  • Codon, Initiator
  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-5