2. Academic Validation
  3. La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)

La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1)

  • J Biol Chem. 2015 Jun 26;290(26):15996-6020. doi: 10.1074/jbc.M114.621730.
Bruno D Fonseca 1,  Chadi Zakaria 2,  Jian-Jun Jia 3,  Tyson E Graber 4,  Yuri Svitkin 2,  Soroush Tahmasebi 2,  Danielle Healy 3,  Huy-Dung Hoang 3,  Jacob M Jensen 5,  Ilo T Diao 5,  Alexandre Lussier 2,  Christopher Dajadian 2,  Niranjan Padmanabhan 2,  Walter Wang 2,  Edna Matta-Camacho 2,  Jaclyn Hearnden 2,  Ewan M Smith 6,  Yoshinori Tsukumo 2,  Akiko Yanagiya 2,  Masahiro Morita 2,  Emmanuel Petroulakis 7,  Jose L González 8,  Greco Hernández 8,  Tommy Alain 9,  Christian K Damgaard 10
Affiliations

Affiliations

  • 1 From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, [email protected].
  • 2 the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • 3 From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
  • 4 From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
  • 5 the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
  • 6 the Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
  • 7 the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada, Pfizer Canada Inc., Kirkland, Quebec H9J 2M5, Canada, and.
  • 8 the Division of Basic Science, National Institute of Cancer, 22 San Fernando Ave., Tlalpan, Mexico City 14080, Mexico.
  • 9 From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, [email protected].
  • 10 the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark, [email protected].
PMID: 25940091 DOI: 10.1074/jbc.M114.621730
Abstract

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.

Keywords

5'-terminal oligopyrimidine (5'TOP) motif; La-related protein 1 (LARP1); TOP mRNA translation; gene expression; mTOR complex 1 (mTORC1); mammalian target of rapamycin (mTOR); protein synthesis; repressor protein; ribosome biogenesis; translation.

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