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 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.
From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, brunodfonseca@gmail.com.
Bruno D
BD
Fonseca
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Chadi
C
Zakaria
From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
Jian-Jun
JJ
Jia
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.
Tyson E
TE
Graber
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Yuri
Y
Svitkin
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Soroush
S
Tahmasebi
From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
Danielle
D
Healy
From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
Huy-Dung
HD
Hoang
the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
Jacob M
JM
Jensen
the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
Ilo T
IT
Diao
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Alexandre
A
Lussier
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Christopher
C
Dajadian
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Niranjan
N
Padmanabhan
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Walter
W
Wang
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Edna
E
Matta-Camacho
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Jaclyn
J
Hearnden
the Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Ewan M
EM
Smith
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Yoshinori
Y
Tsukumo
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Akiko
A
Yanagiya
the Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Masahiro
M
Morita
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.
Emmanuel
E
Petroulakis
the Division of Basic Science, National Institute of Cancer, 22 San Fernando Ave., Tlalpan, Mexico City 14080, Mexico.
Jose L
JL
González
the Division of Basic Science, National Institute of Cancer, 22 San Fernando Ave., Tlalpan, Mexico City 14080, Mexico.
Greco
G
Hernández
From the Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada, tommy@arc.cheo.ca.
Tommy
T
Alain
the Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark, ckd@mbg.au.dk.
Christian K
CK
Damgaard
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D062085:RNA, Long Noncoding; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000097585:SS-B Antigen
D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; D039561:Eukaryotic Initiation Factor-4E; D000076222:Mechanistic Target of Rapamycin Complex 1; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D000076223:Regulatory-Associated Protein of mTOR; D012261:Ribonucleoproteins; D058570:TOR Serine-Threonine Kinases; D000097585:SS-B Antigen; C509980:LINC00273 lncRNA, human; C463659:RPTOR protein, human
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