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

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 pro...

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Bibliographic Details
Published in:The Journal of biological chemistry 2015-06, Vol.290 (26), p.15996-16020
Main Authors: Fonseca, Bruno D., Zakaria, Chadi, Jia, Jian-Jun, Graber, Tyson E., Svitkin, Yuri, Tahmasebi, Soroush, Healy, Danielle, Hoang, Huy-Dung, Jensen, Jacob M., Diao, Ilo T., Lussier, Alexandre, Dajadian, Christopher, Padmanabhan, Niranjan, Wang, Walter, Matta-Camacho, Edna, Hearnden, Jaclyn, Smith, Ewan M., Tsukumo, Yoshinori, Yanagiya, Akiko, Morita, Masahiro, Petroulakis, Emmanuel, González, Jose L., Hernández, Greco, Alain, Tommy, Damgaard, Christian K.
Format: Article
Language:English
Subjects:
5'-terminal oligopyrimidine (5'TOP) motif
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Autoantigens - genetics
Autoantigens - metabolism
Down-Regulation
Eukaryotic Initiation Factor-4E - genetics
Eukaryotic Initiation Factor-4E - metabolism
gene expression
Humans
La-related protein 1 (LARP1)
mammalian target of rapamycin (mTOR)
Mechanistic Target of Rapamycin Complex 1
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
mTOR complex 1 (mTORC1)
Multiprotein Complexes - genetics
Multiprotein Complexes - metabolism
Protein Binding
Protein Biosynthesis
protein synthesis
Protein Synthesis and Degradation
Regulatory-Associated Protein of mTOR
repressor protein
Ribonucleoproteins - genetics
Ribonucleoproteins - metabolism
ribosome biogenesis
RNA, Long Noncoding
RNA, Messenger - chemistry
RNA, Messenger - genetics
RNA, Messenger - metabolism
SS-B Antigen
TOP mRNA translation
TOR Serine-Threonine Kinases - genetics
TOR Serine-Threonine Kinases - metabolism
translation
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Summary: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. Background: mTORC1 plays an important role in the regulation of TOP mRNA translation. Results: LARP1 is a target of mTORC1 that associates with TOP mRNAs via their 5′TOP motif to repress their translation. Conclusion: LARP1 represses TOP mRNA translation downstream of mTORC1. Significance: We elucidate an important novel signaling pathway downstream of mTORC1 that controls the production of ribosomes and translation factors in eukaryotic cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.621730