The translation regulatory subunit eIF3f controls the kinase-dependent mTOR signaling required for muscle differentiation and hypertrophy in mouse.
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.
Csibi
Alfredo
A
Laboratoire de Génomique Fonctionnelle et Myogenèse, UMR866 Différenciation Cellulaire et Croissance, SupAgro-INRA, Montpellier, France.
Cornille
Karen
K
Leibovitch
Marie-Pierre
MP
Poupon
Anne
A
Tintignac
Lionel A
LA
Sanchez
Anthony M J
AM
Leibovitch
Serge A
SA
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
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