Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation

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Abstract
Translation initiation is influenced by input from extracellular stimuli. While two eukaryotic initiation factors (eIFs) are known to transduce external signals to the small (40S) ribosomal subunit, it was not known whether an eIF served a similar function for the large (60S) ribosomal subunit. In this study, Gandin et al. show that eIF6 communicates extracellular signals to the 60S subunit. Cells from an eIF6 heterozygous mouse show normal ribosome assembly but reduced translation, delayed cell cycle progression, and impaired transformation. This work suggests that eIF6 acts an initiation factor, in vivo, and may control growth and tumorigenesis. Although two eukaryotic initiation factors (eIFs) are known to transmit signals to the small ribosomal subunit, it was unknown whether an eIF served a similar function for the large ribosomal subunit. This study shows that eIF6 communicates extracellular signals to the 60S subunit. Cells from an eIF6 heterozygous mouse show normal ribosome biogenesis but reduced translation, delayed cell cycle progression, and impaired transformation. Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation1,2. So far, only two eIFs connect extracellular stimuli to global translation rates3: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors4,5, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli6,7. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro8,9,10. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation11,12,13,14. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6+/- cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6+/- mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6+/- cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.