The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP.
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.
Napoli
Ilaria
I
Department of Biology, University Tor Vergata, Rome, Italy.
Mercaldo
Valentina
V
Boyl
Pietro Pilo
PP
Eleuteri
Boris
B
Zalfa
Francesca
F
De Rubeis
Silvia
S
Di Marino
Daniele
D
Mohr
Evita
E
Massimi
Marzia
M
Falconi
Mattia
M
Witke
Walter
W
Costa-Mattioli
Mauro
M
Sonenberg
Nahum
N
Achsel
Tilmann
T
Bagni
Claudia
C
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
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