The Fragile X Syndrome Protein Represses Activity-Dependent Translation through CYFIP1, a New 4E-BP

Ilaria Napoli, Valentina Mercaldo, Pietro Pilo Boyl, Boris Eleuteri, Francesca Zalfa, Silvia De Rubeis, Daniele Di Marino, Evita Mohr, Marzia Massimi, Mattia Falconi, Walter Witke, Mauro Costa-Mattioli, Nahum Sonenberg, Tilmann Achsel, Claudia Bagni

Research output: Contribution to journalArticlepeer-review

437 Scopus citations

Abstract

Strong evidence indicates that regulated mRNA translation in neuronal dendrites underlies synaptic plasticity and brain development. The fragile X mental retardation protein (FMRP) is involved in this process; here, we show that it acts by inhibiting translation initiation. A binding partner of FMRP, CYFIP1/Sra1, directly binds the translation initiation factor eIF4E through a domain that is structurally related to those present in 4E-BP translational inhibitors. Brain cytoplasmic RNA 1 (BC1), another FMRP binding partner, increases the affinity of FMRP for the CYFIP1-eIF4E complex in the brain. Levels of proteins encoded by known FMRP target mRNAs are increased upon reduction of CYFIP1 in neurons. Translational repression is regulated in an activity-dependent manner because BDNF or DHPG stimulation of neurons causes CYFIP1 to dissociate from eIF4E at synapses, thereby resulting in protein synthesis. Thus, the translational repression activity of FMRP in the brain is mediated, at least in part, by CYFIP1.

Original languageEnglish
Pages (from-to)1042-1054
Number of pages13
JournalCell
Volume134
Issue number6
DOIs
StatePublished - 19 Sep 2008
Externally publishedYes

Keywords

  • HUMDISEASE
  • MOLNEURO
  • PROTEINS

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