FMRP phosphorylation modulates neuronal translation through YTHDF1
Zhongyu Zou, Jiangbo Wei, Yantao Chen, Yunhee Kang, Hailing Shi, Fan Yang, Zhuoyue Shi, Shijie Chen, Ying Zhou, Caraline Sepich‐Poore, Xiaoxi Zhuang, Xiaoming Zhou, Hualiang Jiang, Zhexing Wen, Peng Jin, Cheng Luo, Chuan He
Abstract
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.