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

Leiming Tang, Jacob Morris, Ji Wan, Chelsea Moore, Yoshihiko Fujita, Sarah Gillaspie, Eric Aube, Jagpreet Nanda, Maud Marques, Maika Jangal, Abbey Anderson, Christian Cox, Hiroyuki Hiraishi, Leiming Dong, Hirohide Saito, Chingakham Ranjit Singh, Michael Witcher, Ivan Topisirovic, Shu Bing Qian, Katsura Asano

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

In the human genome, translation initiation fromnon- 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 ofNAT1/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, AUGinitiated isoforms. We propose that the homeostasis of the non-AUG translatome is maintained through balanced expression of eIF5 and 5MP.

Original languageEnglish (US)
Pages (from-to)11941-11953
Number of pages13
JournalNucleic acids research
Volume45
Issue number20
DOIs
StatePublished - Nov 16 2017

All Science Journal Classification (ASJC) codes

  • Genetics

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