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

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DOI

  • Jian-Jun Jia, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Roni M Lahr, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • ,
  • Michael T Solgaard
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  • Bruno J Moraes, Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
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  • Roberta Pointet, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • An-Dao Yang, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Giovanna Celucci, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Tyson E Graber, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Huy-Dung Hoang, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Marius R Niklaus, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Izabella A Pena, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Anne K Hollensen
  • Ewan M Smith, Cancer Research UK Beatson Institute
  • ,
  • Malik Chaker-Margot, Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
  • ,
  • Leonie Anton, Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
  • ,
  • Christopher Dajadian, McGill Univ, McGill University, McGill Space Inst
  • ,
  • Mark Livingstone, McGill Univ, McGill University, McGill Space Inst
  • ,
  • Jaclyn Hearnden, McGill Univ, McGill University, McGill Space Inst
  • ,
  • Xu-Dong Wang, UT Southwestern Medical Center (M.K.J.)
  • ,
  • Yonghao Yu, UT Southwestern Medical Center (M.K.J.)
  • ,
  • Timm Maier, Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
  • ,
  • Christian K Damgaard
  • Andrea J Berman, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • ,
  • Tommy Alain, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
  • ,
  • Bruno D Fonseca, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg

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.

OriginalsprogEngelsk
TidsskriftNucleic Acids Research
Vol/bind49
Nummer6
Sider (fra-til)3461-3489
Antal sider29
ISSN0305-1048
DOI
StatusUdgivet - apr. 2021

Bibliografisk note

© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

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