The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP
The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP
复制标题
DOI：
10.1016/j.cell.2008.07.031
复制
发表时间：
2008-09-19
期刊：
影响因子：
64.5
通讯作者：
Bagni, Claudia
中科院分区：
文献类型：
--
作者：
Napoli, Ilaria;Mercaldo, Valentina;Bagni, Claudia
强有力的证据表明，在神经元树突的调节mRNA的翻译突触可塑性和大脑发育的基础。脆性X智力低下蛋白（FMRP）参与这一过程，在这里，我们表明，它的行为抑制翻译起始。FMRP的结合伴侣CYFIP 1/Sra 1通过结构上与4 E-BP翻译抑制剂中存在的结构域相关的结构域直接结合翻译起始因子eIF 4 E。脑细胞质RNA 1（BC 1），另一种FMRP结合伴侣，增加FMRP对脑中CYFIP 1-eIF 4 E复合物的亲和力。由已知FMRP靶mRNA编码的蛋白质水平在神经元中CYFIP 1减少时增加。翻译抑制以活性依赖性方式调节，因为神经元的BDNF或DHPG刺激导致CYFIP 1在突触处与eIF 4 E解离，从而导致蛋白质合成。因此，脑中FMRP的翻译抑制活性至少部分由CYFIP 1介导。
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.