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La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1)

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DOI

  • Bruno Fonseca, Children's Hospital of Eastern Ontario Research Institute, Canada
  • Chadi Zakaria, McGill University, Canada
  • J J Jia, Children's Hospital of Eastern Ontario Research Institute, Canada
  • T E Graber, Children's Hospital of Eastern Ontario Research Institute, Canada
  • Yuri Svitkin, McGill University, Canada
  • S Tahmasebi, McGill University, Montreal, Canada, Canada
  • D Healy, Children's Hospital of Eastern Ontario Research Institute, Canada
  • HD Hoang, Children's Hospital of Eastern Ontario Research Institute, Canada
  • Jacob Malte Jensen
  • Ilo Thrane Diao, Denmark
  • A Lussier, McGill University, Montreal, Canada, Canada
  • C Dajadian, McGill University, Montreal, Canada, Canada
  • N Padmanabhan , McGill University, Montreal, Canada, Canada
  • W Wang, McGill University, Montreal, Canada, Canada
  • Edna Matta-Camacho, McGill University, Montreal, Canada, Canada
  • J Hearnden, McGill University, Montreal, Canada, Canada
  • EM Smith, MRC Toxicology Unit, United Kingdom
  • Y Tsukumo , McGill University, Montreal, Canada, Canada
  • A Yanagiya, McGill University, Montreal, Canada, Canada
  • M Morita, McGill University, Montreal, Canada, Canada
  • E Petroulakis, McGill University, Montreal, Canada, Canada
  • JL Gonzalez, National Institute of Cancer, Mexico
  • G Hernandez, National Institute of Cancer, Mexico
  • Tommy Alain, Children's Hospital of Eastern Ontario Research Institute, Canada
  • Christian Kroun Damgaard
The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5′TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume290
Pages (from-to)15996-16020
Number of pages24
ISSN0021-9258
DOIs
Publication statusPublished - 26 Jun 2015

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