Cargando…
A unifying model for mTORC1-mediated regulation of mRNA translation
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(1). mTORC1 regulates mRNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/ https://www.ncbi.nlm.nih.gov/pubmed/22552098 http://dx.doi.org/10.1038/nature11083 |
_version_ | 1782232322678980608 |
---|---|
author | Thoreen, Carson C. Chantranupong, Lynne Keys, Heather R. Wang, Tim Gray, Nathanael S. Sabatini, David M. |
author_facet | Thoreen, Carson C. Chantranupong, Lynne Keys, Heather R. Wang, Tim Gray, Nathanael S. Sabatini, David M. |
author_sort | Thoreen, Carson C. |
collection | PubMed |
description | 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(1). 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 mTORC1(2). 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 complexity(3). mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown(4). 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. |
format | Online Article Text |
id | pubmed-3347774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
record_format | MEDLINE/PubMed |
spelling | pubmed-33477742012-11-03 A unifying model for mTORC1-mediated regulation of mRNA translation Thoreen, Carson C. Chantranupong, Lynne Keys, Heather R. Wang, Tim Gray, Nathanael S. Sabatini, David M. Nature Article 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(1). 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 mTORC1(2). 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 complexity(3). mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown(4). 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. 2012-05-02 /pmc/articles/PMC3347774/ /pubmed/22552098 http://dx.doi.org/10.1038/nature11083 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Thoreen, Carson C. Chantranupong, Lynne Keys, Heather R. Wang, Tim Gray, Nathanael S. Sabatini, David M. A unifying model for mTORC1-mediated regulation of mRNA translation |
title | A unifying model for mTORC1-mediated regulation of mRNA translation |
title_full | A unifying model for mTORC1-mediated regulation of mRNA translation |
title_fullStr | A unifying model for mTORC1-mediated regulation of mRNA translation |
title_full_unstemmed | A unifying model for mTORC1-mediated regulation of mRNA translation |
title_short | A unifying model for mTORC1-mediated regulation of mRNA translation |
title_sort | unifying model for mtorc1-mediated regulation of mrna translation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/ https://www.ncbi.nlm.nih.gov/pubmed/22552098 http://dx.doi.org/10.1038/nature11083 |
work_keys_str_mv | AT thoreencarsonc aunifyingmodelformtorc1mediatedregulationofmrnatranslation AT chantranuponglynne aunifyingmodelformtorc1mediatedregulationofmrnatranslation AT keysheatherr aunifyingmodelformtorc1mediatedregulationofmrnatranslation AT wangtim aunifyingmodelformtorc1mediatedregulationofmrnatranslation AT graynathanaels aunifyingmodelformtorc1mediatedregulationofmrnatranslation AT sabatinidavidm aunifyingmodelformtorc1mediatedregulationofmrnatranslation AT thoreencarsonc unifyingmodelformtorc1mediatedregulationofmrnatranslation AT chantranuponglynne unifyingmodelformtorc1mediatedregulationofmrnatranslation AT keysheatherr unifyingmodelformtorc1mediatedregulationofmrnatranslation AT wangtim unifyingmodelformtorc1mediatedregulationofmrnatranslation AT graynathanaels unifyingmodelformtorc1mediatedregulationofmrnatranslation AT sabatinidavidm unifyingmodelformtorc1mediatedregulationofmrnatranslation |