eIF3 Associates with 80S Ribosomes to Promote Translation Elongation, Mitochondrial Homeostasis, and Muscle Health

Mol Cell. 2020 Aug 20;79(4):575-587.e7. doi: 10.1016/j.molcel.2020.06.003. Epub 2020 Jun 25.

Abstract

eIF3, a multi-subunit complex with numerous functions in canonical translation initiation, is known to interact with 40S and 60S ribosomal proteins and translation elongation factors, but a direct involvement in translation elongation has never been demonstrated. We found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote elongation, eIF3 interacts with 80S ribosomes translating the first ∼60 codons and serves to recruit protein quality-control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e+/- mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength. Hence, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health.

Keywords: eIF3; knockout mouse; mRNA translation; mitochondrial protein synthesis; muscle strength; ribosome profiling; selective ribosome profiling; translation elongation; translation initiation; translation initiation factor 3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Eukaryotic Initiation Factor-3 / genetics
  • Eukaryotic Initiation Factor-3 / metabolism*
  • HeLa Cells
  • Humans
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Peptide Chain Elongation, Translational*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribosome Subunits / genetics
  • Ribosome Subunits / metabolism

Substances

  • Eukaryotic Initiation Factor-3
  • Mitochondrial Proteins
  • RNA, Messenger