DENR•MCT-1 Promotes Translation Reinitiation Downstream of uORFs to Control Tissue Growth

During cap-dependent eukaryotic translation initiation, ribosomes scan mRNA from the 5′ end to the first AUG start codon with favorable 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 reinitiation, an incompletely understood process(1,4-6). Reinitiation is thought to involve the same factors as standard initiation(1,5,7). It is unknown if any factors specifically affect translation reinitiation without affecting standard cap-dependent translation. We uncover here the non-canonical initiation factors Density Regulated Protein (DENR) and Multiple Copies in T-cell Lymphoma-1 (MCT-1) as the first selective regulators of eukaryotic reinitiation. mRNAs containing upstream Open Reading Frames with strong Kozak sequences (stuORFs) 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.