title: The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP.
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.
authors.affiliation: Department of Biology, University Tor Vergata, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Napoli
authors.forename: Valentina
authors.initials: V
authors.lastname: Mercaldo
authors.forename: Pietro Pilo
authors.initials: PP
authors.lastname: Boyl
authors.forename: Boris
authors.initials: B
authors.lastname: Eleuteri
authors.forename: Francesca
authors.initials: F
authors.lastname: Zalfa
authors.forename: Silvia
authors.initials: S
authors.lastname: De Rubeis
authors.forename: Daniele
authors.initials: D
authors.lastname: Di Marino
authors.forename: Evita
authors.initials: E
authors.lastname: Mohr
authors.forename: Marzia
authors.initials: M
authors.lastname: Massimi
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.forename: Walter
authors.initials: W
authors.lastname: Witke
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Tilmann
authors.initials: T
authors.lastname: Achsel
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D002478:Cells, Cultured; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D014176:Protein Biosynthesis; D016415:Sequence Alignment; D013569:Synapses
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D039561:Eukaryotic Initiation Factor-4E; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; C115472:Cyfip1 protein, mouse; C497684:Fmr1 protein, mouse