Novel FMRP interaction networks linked to cellular stress

FEBS J. 2021 Feb;288(3):837-860. doi: 10.1111/febs.15443. Epub 2020 Jun 23.


Silencing of the fragile X mental retardation 1 (FMR1) gene and consequently lack of synthesis of FMR protein (FMRP) are associated with fragile X syndrome, which is one of the most prevalent inherited intellectual disabilities, with additional roles in increased viral infection, liver disease, and reduced cancer risk. FMRP plays critical roles in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation. However, the underlying molecular mechanisms, including the (sub)cellular FMRP protein networks, remain elusive. Here, we employed affinity pull-down and quantitative LC-MS/MS analyses with FMRP. We identified known and novel candidate FMRP-binding proteins as well as protein complexes. FMRP interacted with 180 proteins, 28 of which interacted with its N terminus. Interaction with the C terminus of FMRP was observed for 102 proteins, and 48 proteins interacted with both termini. This FMRP interactome comprises known FMRP-binding proteins, including the ribosomal proteins FXR1P, NUFIP2, Caprin-1, and numerous novel FMRP candidate interacting proteins that localize to different subcellular compartments, including CARF, LARP1, LEO1, NOG2, G3BP1, NONO, NPM1, SKIP, SND1, SQSTM1, and TRIM28. Our data considerably expand the protein and RNA interaction networks of FMRP, which thereby suggest that, in addition to its known functions, FMRP participates in transcription, RNA metabolism, ribonucleoprotein stress granule formation, translation, DNA damage response, chromatin dynamics, cell cycle regulation, ribosome biogenesis, miRNA biogenesis, and mitochondrial organization. Thus, FMRP seems associated with multiple cellular processes both under normal and cell stress conditions in neuronal as well as non-neuronal cell types, as exemplified by its role in the formation of stress granules.

Keywords: FMRP; RNA-binding; fragile X mental retardation protein; protein interaction network; stress granule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Chromatography, Liquid / methods
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nucleophosmin
  • Protein Binding
  • Protein Interaction Maps*
  • RNA / genetics
  • RNA / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Stress, Physiological*
  • Tandem Mass Spectrometry / methods


  • CAPRIN1 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • FXR1 protein, human
  • NPM1 protein, human
  • NUFIP2 protein, human
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Nucleophosmin
  • Fragile X Mental Retardation Protein
  • RNA