title: Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation.
abstract: The mammalian target of rapamycin (mTOR) promotes cell growth and proliferation by promoting mRNA translation and increasing the protein synthetic capacity of the cell. Although mTOR globally promotes translation by regulating the mRNA 5' cap-binding protein eIF4E (eukaryotic initiation factor 4E), it also preferentially regulates the translation of certain classes of mRNA via unclear mechanisms. To help fill this gap in knowledge, we performed a quantitative proteomic screen to identify proteins that associate with the mRNA 5' cap in an mTOR-dependent manner. Using this approach, we identified many potential regulatory factors, including the putative RNA-binding protein LARP1 (La-related protein 1). Our results indicate that LARP1 associates with actively translating ribosomes via PABP and that LARP1 stimulates the translation of mRNAs containing a 5' terminal oligopyrimidine (TOP) motif, encoding for components of the translational machinery. We found that LARP1 associates with the mTOR complex 1 (mTORC1) and is required for global protein synthesis as well as cell growth and proliferation. Together, these data reveal important molecular mechanisms involved in TOP mRNA translation and implicate LARP1 as an important regulator of cell growth and proliferation.
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada;
authors.forename: Joseph
authors.initials: J
authors.lastname: Tcherkezian
authors.forename: Marie
authors.initials: M
authors.lastname: Cargnello
authors.forename: Yves
authors.initials: Y
authors.lastname: Romeo
authors.forename: Edward L
authors.initials: EL
authors.lastname: Huttlin
authors.forename: Genevieve
authors.initials: G
authors.lastname: Lavoie
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Roux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D040901:Proteomics; D011743:Pyrimidines / Q000378:metabolism*; D039381:RNA Cap-Binding Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000097585:SS-B Antigen
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; D011743:Pyrimidines; D039381:RNA Cap-Binding Proteins; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D058570:TOR Serine-Threonine Kinases; D000097585:SS-B Antigen; C030986:pyrimidine
keywords: 5′TOP; LARP1; mRNA; mTOR; proteomics; translation