A unifying model for mTORC1-mediated regulation of mRNA translation

By C. Thoreen, Lynne Chantranupong, Heather R. Keys, Tim Wang, Nathanael S. Gray, David M. Sabatini. Nature, 2012

1,466 citations recorded by the source corpus.

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 uses. mTORC1 regulates messenger RNA 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 mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model 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′ untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4E-BP family of translational repressors, arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin 1. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e612fddd19477360a52fbb8b649744ef87a5ff5f

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Citations in the corpus

Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “81 The mTORC1 phosphorylates its substrate 4EBP that triggers its dissociation from eIF4E allowing 5 ′ cap-dependent mRNA translation (Figs.”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Global ribosome footprinting analyses, however, revealed that, while acutemTOR inhibitionmoderately suppresses general mRNA translation, it most profoundly affects mRNAs containing pyrimidine-rich 50 TOP or ‘‘TOP-like’’ motifs, which includes most genes involved in protein synthesis (Hsieh et al., 2”
mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. (2013, background): “Consistent with previous findings (Alain et al., 2012; Hsieh et al., 2012; Thoreen et al., 2012), Ink1341 and Torin1 did not induce complete disassembly of polysomes (Figure 2C), indicating that these compounds selectively block translation of a subset of mRNAs.”
Pharmacological brake-release of mRNA translation enhances cognitive memory (2013, methodology): “To this end we used Torin-1, an inhibitor of mTOR that blocks phosphorylation of 4E-BP1 and S6K1, and leads to translational attenuation (Thoreen et al., 2012).”
Toward a Kinetic Understanding of Eukaryotic Translation. (2018, background): “Immunoprecipitation assays have indicated that the affinity of eIF4G binding to eIF3 is enhanced by TORC1 activation by a yet-to-be-determined mechanism (Harris et al. 2006; Thoreen et al. 2012).”
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype (2015, positive): “The global translation rate increased during OIS and, in agreement with previous studies 20 , treatment with Torin1 greatly reduced de novo protein synthesis.”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “…analyses however revealed that while acute mTOR inhibition moderately suppresses general mRNA translation, it most profoundly affects mRNAs containing pyrimidine-rich 5′ TOP or “TOP-like” motifs, which includes most genes involved in protein synthesis (Hsieh et al. 2012; Thoreen et al. 2012).”