Molecular cell · 2023
FMRP phosphorylation modulates neuronal translation through YTHDF1.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.