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FMRP phosphorylation modulates neuronal translation through YTHDF1
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DOI：10.1016/j.molcel.2023.10.028.png)
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Abstract
En 中文
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 tar-gets. FMRP regulates this process by sequestering YTHDF1 away from the ribosome; upon neuronal stimu-lation, 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:
FRAGILE-X-SYNDROME
MESSENGER-RNA TRANSLATION
LOCAL PROTEIN-SYNTHESIS
MEMORY
ORGANOIDS
BINDING
KINASE
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