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

Bruno D. Fonseca, Chadi Zakaria, Jian Jun Jia, Tyson E. Graber, Yuri Svitkin, Soroush Tahmasebi, Danielle Healy, Huy Dung Hoang, Jacob M. Jensen, Ilo T. Diao, Alexandre Lussier, Christopher Dajadian, Niranjan Padmanabhan, Walter Wang, Edna Matta-Camacho, Jaclyn Hearnden, Ewan M. Smith, Yoshinori Tsukumo, Akiko Yanagiya, Masahiro MoritaEmmanuel Petroulakis, Jose L. González, Greco Hernández, Tommy Alain, Christian K. Damgaard

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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 factorbinding 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) LARP1associates 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 (US)
Pages (from-to)15996-16020
Number of pages25
JournalJournal of Biological Chemistry
Volume290
Issue number26
DOIs
StatePublished - Jun 26 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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