title: The translation regulatory subunit eIF3f controls the kinase-dependent mTOR signaling required for muscle differentiation and hypertrophy in mouse.
abstract: The mTORC1 pathway is required for both the terminal muscle differentiation and hypertrophy by controlling the mammalian translational machinery via phosphorylation of S6K1 and 4E-BP1. mTOR and S6K1 are connected by interacting with the eIF3 initiation complex. The regulatory subunit eIF3f plays a major role in muscle hypertrophy and is a key target that accounts for MAFbx function during atrophy. Here we present evidence that in MAFbx-induced atrophy the degradation of eIF3f suppresses S6K1 activation by mTOR, whereas an eIF3f mutant insensitive to MAFbx polyubiquitination maintained persistent phosphorylation of S6K1 and rpS6. During terminal muscle differentiation a conserved TOS motif in eIF3f connects mTOR/raptor complex, which phosphorylates S6K1 and regulates downstream effectors of mTOR and Cap-dependent translation initiation. Thus eIF3f plays a major role for proper activity of mTORC1 to regulate skeletal muscle size.
authors.affiliation: Laboratoire de Génomique Fonctionnelle et Myogenèse, UMR866 Différenciation Cellulaire et Croissance, SupAgro-INRA, Montpellier, France.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Csibi
authors.forename: Karen
authors.initials: K
authors.lastname: Cornille
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Leibovitch
authors.forename: Anne
authors.initials: A
authors.lastname: Poupon
authors.forename: Lionel A
authors.initials: LA
authors.lastname: Tintignac
authors.forename: Anthony M J
authors.initials: AM
authors.lastname: Sanchez
authors.forename: Serge A
authors.initials: SA
authors.lastname: Leibovitch
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002454:Cell Differentiation; D049108:Cell Enlargement; D002478:Cells, Cultured; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins; D034622:RNA Interference; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D039621:Eukaryotic Initiation Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D011506:Proteins; D014157:Transcription Factors; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D008239:Lysine