The translation regulatory subunit eIF3f controls the kinase-dependent mTOR signaling required for muscle differentiation and hypertrophy in mouse

PLoS One. 2010 Feb 1;5(2):e8994. doi: 10.1371/journal.pone.0008994.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Differentiation
  • Cell Enlargement
  • Cells, Cultured
  • Eukaryotic Initiation Factor-3 / genetics
  • Eukaryotic Initiation Factor-3 / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lysine / genetics
  • Lysine / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Mutation
  • Myoblasts, Skeletal / cytology
  • Myoblasts, Skeletal / metabolism*
  • Protein Binding
  • Protein Biosynthesis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteins
  • RNA Interference
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Satellite Cells, Skeletal Muscle / cytology
  • Satellite Cells, Skeletal Muscle / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection

Substances

  • Eukaryotic Initiation Factor-3
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Muscle Proteins
  • Proteins
  • Transcription Factors
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • TOR Serine-Threonine Kinases
  • Lysine