FMRP phosphorylation modulates neuronal translation through YTHDF1.
FMRP phosphorylation modulates neuronal translation through YTHDF1.
复制标题
FMRP 磷酸化通过 YTHDF1 调节神经元翻译。
DOI：
10.1016/j.molcel.2023.10.028
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发表时间：
2023
期刊：
影响因子：
16
通讯作者：
He,Chuan
中科院分区：
文献类型：
--
作者：
Zou,Zhongyu;Wei,Jiangbo;Chen,Yantao;Kang,Yunhee;Shi,Hailing;Yang,Fan;Shi,Zhuoyue;Chen,Shijie;Zhou,Ying;Sepich-Poore,Caraline;Zhuang,Xiaoxi;Zhou,Xiaoming;Jiang,Hualiang;Wen,Zhexing;Jin,Peng;Luo,Cheng;He,Chuan
RNA结合蛋白（RBP）控制神经元中信使RNA的命运。在这里，我们报告了一种机制，刺激诱导的神经元翻译介导的磷酸化YTHDF 1结合蛋白FMRP。从机制上讲，YTHDF 1可以与核糖体蛋白质缩合，以促进其mRNA靶标的翻译。FMRP通过将YTHDF 1与核糖体隔离来调节这一过程;在神经元刺激时，FMRP变得磷酸化并释放YTHDF 1用于翻译上调。我们发现，一种新的YTHDF 1小分子抑制剂可以逆转类器官模型中与FMRP缺乏相关的脆性X综合征（FXS）发育缺陷。因此，我们的研究表明，FMRP及其磷酸化是神经元发育和刺激过程中活性依赖性翻译的重要调节因子，并将YTHDF 1确定为FXS的潜在治疗靶点，其中FMRP缺失引起的发育缺陷可以通过YTHDF 1抑制来逆转。
RNA-binding proteins (RBPs) control messenger RNA fate in neurons. Here, we report a mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Mechanistically, YTHDF1 can condense with ribosomal proteins to promote the translation of its mRNA targets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimulation, FMRP becomes phosphorylated and releases YTHDF1 for translation upregulation. We show that a new small molecule inhibitor of YTHDF1 can reverse fragile X syndrome (FXS) developmental defects associated with FMRP deficiency in an organoid model. Our study thus reveals that FMRP and its phosphorylation are important regulators of activity-dependent translation during neuronal development and stimulation and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.