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LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs

The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5’TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5’TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated tra...

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Autores principales: Hong, Sungki, Freeberg, Mallory A, Han, Ting, Kamath, Avani, Yao, Yao, Fukuda, Tomoko, Suzuki, Tsukasa, Kim, John K, Inoki, Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484620/
https://www.ncbi.nlm.nih.gov/pubmed/28650797
http://dx.doi.org/10.7554/eLife.25237
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author Hong, Sungki
Freeberg, Mallory A
Han, Ting
Kamath, Avani
Yao, Yao
Fukuda, Tomoko
Suzuki, Tsukasa
Kim, John K
Inoki, Ken
author_facet Hong, Sungki
Freeberg, Mallory A
Han, Ting
Kamath, Avani
Yao, Yao
Fukuda, Tomoko
Suzuki, Tsukasa
Kim, John K
Inoki, Ken
author_sort Hong, Sungki
collection PubMed
description The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5’TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5’TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5’ and 3’UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3’UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis. DOI: http://dx.doi.org/10.7554/eLife.25237.001
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spelling pubmed-54846202017-07-18 LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs Hong, Sungki Freeberg, Mallory A Han, Ting Kamath, Avani Yao, Yao Fukuda, Tomoko Suzuki, Tsukasa Kim, John K Inoki, Ken eLife Biochemistry The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5’TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5’TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5’ and 3’UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3’UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis. DOI: http://dx.doi.org/10.7554/eLife.25237.001 eLife Sciences Publications, Ltd 2017-06-26 /pmc/articles/PMC5484620/ /pubmed/28650797 http://dx.doi.org/10.7554/eLife.25237 Text en © 2017, Hong et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry
Hong, Sungki
Freeberg, Mallory A
Han, Ting
Kamath, Avani
Yao, Yao
Fukuda, Tomoko
Suzuki, Tsukasa
Kim, John K
Inoki, Ken
LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs
title LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs
title_full LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs
title_fullStr LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs
title_full_unstemmed LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs
title_short LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs
title_sort larp1 functions as a molecular switch for mtorc1-mediated translation of an essential class of mrnas
topic Biochemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484620/
https://www.ncbi.nlm.nih.gov/pubmed/28650797
http://dx.doi.org/10.7554/eLife.25237
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