The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP.

By I. Napoli, Valentina Mercaldo, P. P. Boyl, B. Eleuteri, F. Zalfa, Silvia De Rubeis, D. Marino, E. Mohr, M. Massimi, M. Falconi and 5 more. Cell, 2008

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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.

Subfields: Cell Biology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c60ab8ba09ff4b3e619cb3c1319d79011118d8dd

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Citations in the corpus

Translational control of long-lasting synaptic plasticity and memory. (2009, background): “CYFIP1/Sra-1 competes with eIF4G for binding to eIF4E in a manner similar to 4E-BPs, although not through a canonical eIF4E-binding site (Napoli et al., 2008).”
Fragile X Mental Retardation Protein: A Paradigm for Translational Control by RNA-Binding Proteins (2015, background): “Interestingly, studies showed that Cytoplasmic FMRP Interacting Protein (CYFIP1) interacts with both FMRP and eIF4E to repress translation initiation (Napoli et al., 2008).”
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. (2008, unknown): “An exciting recent study has discovered that CYFIP1, an FMRP interacting protein (Schenck et al., 2001), has a noncanonical eIF4E interacting domain, which forms a translationally dormant mRNP complex with FMRP and associated mRNAs (Napoli et al., 2008).”
De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2011, background): “49 CYFIP1 also regulates translation of CAMKII, 49 a key component of NMDAR complexes.”
Advancing the understanding of autism disease mechanisms through genetics (2016, unknown): “…X mental retardation protein (FMRP) that also regulates neuronal translation 180 , and dup15q11-q13, which contains the FMRP interactor and translational repressor cytoplasmic FMR1-interacting protein 1 ( CYFIP1 ) 181,182 , also suggest convergence on neuronal translational regulation ( Figs.”
BDNF-induced local protein synthesis and synaptic plasticity. (2014, unknown): “However, some of these RNAbinding proteins can also act as translation repressors (Huttelmaier et al., 2005; Jung et al., 2006; Napoli et al., 2008; Richter, 2007), linkers to motor proteins (Dictenberg et al., 2008; Falley et al., 2009) or even regulators of mRNA decay (Kim et al., 2005).”
Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets (2009, unknown): “Although several conflicting models have been proposed to explain the mechanism of translational repression by FMRP (reviewed in Klann and Richter, 2007), it was recently reported that FMRP binds to eIF4E via CYFIP1 (cytoplasmic FMRP interacting protein 1), thus displacing eIF4G and consequently inh”