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.

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