FMRP Phosphorylation Modulates Neuronal Translation Through YTHDF1

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Nov 10

PMID 37949069

Authors

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

Affiliations

Soon will be listed here.

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.

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