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

doi:10.1016/j.molcel.2023.10.028

FMRP phosphorylation modulates neuronal translation through YTHDF1

Mol Cell. 2023 Dec 7;83(23):4304-4317.e8. doi: 10.1016/j.molcel.2023.10.028. Epub 2023 Nov 9.

Authors

Zhongyu Zou¹, Jiangbo Wei¹, Yantao Chen², Yunhee Kang³, Hailing Shi¹, Fan Yang¹, Zhuoyue Shi⁴, Shijie Chen⁵, Ying Zhou³, Caraline Sepich-Poore⁶, Xiaoxi Zhuang⁷, Xiaoming Zhou⁸, Hualiang Jiang², Zhexing Wen³, Peng Jin⁹, Cheng Luo¹⁰, Chuan He¹¹

Affiliations

¹ Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
² The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Department of Psychiatry and Behavioral Sciences, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁴ Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
⁵ The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
⁶ Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
⁷ Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
⁸ Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
⁹ Department of Psychiatry and Behavioral Sciences, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: peng.jin@emory.edu.
¹⁰ The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: cluo@simm.ac.cn.
¹¹ Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.

PMID: 37949069
PMCID: PMC10872974 (available on 2024-12-07)
DOI: 10.1016/j.molcel.2023.10.028

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.

Keywords: FMRP; RNA-binding proteins; YTHDF1; m(6)A; neuronal translation control; protein condensates.

MeSH terms

Fragile X Mental Retardation Protein* / genetics
Fragile X Mental Retardation Protein* / metabolism
Fragile X Syndrome* / genetics
Fragile X Syndrome* / metabolism
Humans
Neurons / metabolism
Phosphorylation
RNA, Messenger / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Ribosomal Proteins / metabolism

Substances

Fragile X Mental Retardation Protein
Ribosomal Proteins
RNA, Messenger
YTHDF1 protein, human
RNA-Binding Proteins

Abstract

MeSH terms

Substances

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