A Unifying Model for mTORC1-Mediated Regulation of mRNA Translation

Abstract

The mTOR Complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses1. mTORC1 regulates mRNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in cells acutely treated with the mTOR inhibitor Torin1, which, unlike rapamycin, fully inhibits mTORC12. These data reveal a surprisingly simple view of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5′ terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5′ UTR length or complexity3. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown4. Remarkably, loss of just the well-characterized mTORC1 substrates, the 4E-BP family of translational repressors, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin1. The 4E-BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation. Our results clarify the translational program controlled by mTORC1 and identify 4E-BPs and eIF4G1 as its master effectors.