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mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1

Jia, Jian-Jun and Lahr, Roni M. and Solgaard, Michael T. and Moraes, Bruno J. and Pointet, Roberta and Yang, An-Dao and Celucci, Giovanna and Graber, Tyson E. and Hoang, Huy-Dung and Niklaus, Marius R. and Pena, Izabella A. and Hollensen, Anne K. and Smith, Ewan M. and Chaker-Margot, Malik and Anton, Leonie and Dajadian, Christopher and Livingstone, Mark and Hearnden, Jaclyn and Wang, Xu-Dong and Yu, Yonghao and Maier, Timm and Damgaard, Christian K. and Berman, Andrea J. and Alain, Tommy and Fonseca, Bruno D.. (2021) mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1. Nucleic Acids Research, 49 (6). pp. 3461-3489.

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Official URL: https://edoc.unibas.ch/80402/

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Abstract

LARP1 is a key repressor of TOP mRNA translation. It binds the m7Gppp cap moiety and the adjacent 5'TOP motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 controls TOP mRNA translation via LARP1, but the details of the mechanism are unclear. Herein we elucidate the mechanism by which mTORC1 controls LARP1's translation repression activity. We demonstrate that mTORC1 phosphorylates LARP1 in vitro and in vivo, activities that are efficiently inhibited by rapamycin and torin1. We uncover 26 rapamycin-sensitive phospho-serine and -threonine residues on LARP1 that are distributed in 7 clusters. Our data show that phosphorylation of a cluster of residues located proximally to the m7Gppp cap-binding DM15 region is particularly sensitive to rapamycin and regulates both the RNA-binding and the translation inhibitory activities of LARP1. Our results unravel a new model of translation control in which the La module (LaMod) and DM15 region of LARP1, both of which can directly interact with TOP mRNA, are differentially regulated: the LaMod remains constitutively bound to PABP (irrespective of the activation status of mTORC1), while the C-terminal DM15 'pendular hook' engages the TOP mRNA 5'-end to repress translation, but only in conditions of mTORC1 inhibition.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
UniBasel Contributors:Maier, Timm and Chaker-Margot, Malik and Anton, Leonie
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
ISSN:0305-1048
e-ISSN:1362-4962
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:31 Aug 2021 14:08
Deposited On:31 Aug 2021 14:08

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