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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/25237 |
| _version_ | 1811181072181886976 |
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| author | Sungki Hong Mallory A Freeberg Ting Han Avani Kamath Yao Yao Tomoko Fukuda Tsukasa Suzuki John K Kim Ken Inoki |
| author_facet | Sungki Hong Mallory A Freeberg Ting Han Avani Kamath Yao Yao Tomoko Fukuda Tsukasa Suzuki John K Kim Ken Inoki |
| author_sort | Sungki Hong |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T09:13:32Z |
| format | Article |
| id | doaj.art-1be33cf3c8b74fcaae03444cd7d5f0d1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:13:32Z |
| publishDate | 2017-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1be33cf3c8b74fcaae03444cd7d5f0d12022-12-22T04:32:26ZengeLife Sciences Publications LtdeLife2050-084X2017-06-01610.7554/eLife.25237LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAsSungki Hong0Mallory A Freeberg1Ting Han2Avani Kamath3Yao Yao4Tomoko Fukuda5Tsukasa Suzuki6John K Kim7Ken Inoki8https://orcid.org/0000-0001-8882-444XLife Sciences Institute, University of Michigan, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United StatesThe 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.https://elifesciences.org/articles/25237La-related protein 1mTORC1translationAktribosome biogenesisS6K1 |
| spellingShingle | Sungki Hong Mallory A Freeberg Ting Han Avani Kamath Yao Yao Tomoko Fukuda Tsukasa Suzuki John K Kim Ken Inoki LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs eLife La-related protein 1 mTORC1 translation Akt ribosome biogenesis S6K1 |
| 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 | La-related protein 1 mTORC1 translation Akt ribosome biogenesis S6K1 |
| url | https://elifesciences.org/articles/25237 |
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