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

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  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Down-Regulation* ; Protein Biosynthesis*; Autoantigens/*metabolism ; Membrane Glycoproteins/*metabolism ; RNA, Messenger/*genetics ; Ribonucleoproteins/*metabolism; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Autoantigens/genetics ; Eukaryotic Initiation Factor-4E/genetics ; Eukaryotic Initiation Factor-4E/metabolism ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Membrane Glycoproteins/genetics ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Protein Binding ; RNA, Long Noncoding ; RNA, Messenger/chemistry ; RNA, Messenger/metabolism ; Regulatory-Associated Protein of mTOR ; Ribonucleoproteins/genetics ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; SS-B Antigen
    • 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.
      (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
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    • Contributed Indexing:
      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
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Autoantigens)
      0 (Eukaryotic Initiation Factor-4E)
      0 (LINC00273 lncRNA, human)
      0 (Membrane Glycoproteins)
      0 (Multiprotein Complexes)
      0 (RNA, Long Noncoding)
      0 (RNA, Messenger)
      0 (RPTOR protein, human)
      0 (Regulatory-Associated Protein of mTOR)
      0 (Ribonucleoproteins)
      EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
      EC 2.7.11.1 (TOR Serine-Threonine Kinases)
    • Publication Date:
      Date Created: 20150506 Date Completed: 20151002 Latest Revision: 20231213
    • Publication Date:
      20240829
    • Accession Number:
      PMC4481205
    • Accession Number:
      10.1074/jbc.M114.621730
    • Accession Number:
      25940091