DENR–MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth

This study identifies the DENR–MCT-1 complex as the first factors in animals specific for translation re-initiation downstream of upstream Open Reading Frames (uORFs). When the first AUG isn't the last Eukaryotic mRNAs contain a cap structure at their 5′ ends that guides the ribosome to the mRNA. From there, the ribosome translocates towards the 3′ end until it encounters an AUG start codon, at which point it initiates translation. However, for many animal mRNAs, the first AUG is located in a short upstream open reading frame (uORF), which means that translation of the main coding region of the mRNA requires a re-initiation event at its AUG. Aurelio Teleman and colleagues have now identified the first factor specific for this re-initiation process. This initiation factor, DENR, allows bypass of some factors required for canonical, cap-dependent initiation. Some cell proliferation and growth genes that are involved in cancer are dependent on DENR for their translation. During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5′ end to the first AUG start codon with favourable sequence context 1 , 2 . For many mRNAs this AUG belongs to a short upstream open reading frame (uORF) 3 , and translation of the main downstream ORF requires re-initiation, an incompletely understood process 1 , 4 , 5 , 6 . Re-initiation is thought to involve the same factors as standard initiation 1 , 5 , 7 . It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation. Here we uncover the non-canonical initiation factors density regulated protein (DENR) and multiple copies in T-cell lymphoma-1 (MCT-1; also called MCTS1 in humans) as the first selective regulators of eukaryotic re-initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR–MCT-1 for their proper translation, yielding a novel class of mRNAs that can be co-regulated and that is enriched for regulatory proteins such as oncogenic kinases. Collectively, our data reveal that cells have a previously unappreciated translational control system with a key role in supporting proliferation and tissue growth.