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Translational homeostasis via the mRNA cap-binding protein, eIF4E.

Translational control of gene expression plays a key role in many biological processes. Consequently, the activity of the translation apparatus is under tight homeostatic control. eIF4E, the mRNA 5' cap-binding protein, facilitates cap-dependent translation and is a major target for translational control. eIF4E activity is controlled by a family of repressor proteins, termed 4E-binding proteins (4E-BPs). Here, we describe the surprising finding that despite the importance of eIF4E for translation, a drastic knockdown of eIF4E caused only minor reduction in translation. This conundrum can be explained by the finding that 4E-BP1 is degraded in eIF4E-knockdown cells. Hypophosphorylated 4E-BP1, which binds to eIF4E, is degraded, whereas hyperphosphorylated 4E-BP1 is refractory to degradation. We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination.

Pubmed ID: 22578813


  • Yanagiya A
  • Suyama E
  • Adachi H
  • Svitkin YV
  • Aza-Blanc P
  • Imataka H
  • Mikami S
  • Martineau Y
  • Ronai ZA
  • Sonenberg N


Molecular cell

Publication Data

June 29, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: CA51995
  • Agency: Canadian Institutes of Health Research, Id: MOP 7214
  • Agency: NCI NIH HHS, Id: P01 CA128814
  • Agency: NCI NIH HHS, Id: R01 CA051995

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Eukaryotic Initiation Factor-4E
  • HEK293 Cells
  • HeLa Cells
  • Homeostasis
  • Humans
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Phosphoproteins
  • Protein Biosynthesis
  • RNA Cap-Binding Proteins
  • Transfection
  • Ubiquitin