The RNA-binding protein FUS/TLS undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for GRIA2 mRNA processing

J Biol Chem. 2019 Jun 28;294(26):10194-10210. doi: 10.1074/jbc.RA118.005933. Epub 2019 May 15.


Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity included TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS). We noted that FUS is translocated through a calcium-dependent mechanism and that its translocation coincides with striking alterations in nucleocytoplasmic transport. Furthermore, glutamate-induced up-regulation of glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type subunit 2 (GRIA2) in neurons depended on FUS expression, consistent with a functional role for FUS in excitotoxic stress. These findings reveal molecular links among prominent factors in neurodegenerative diseases, namely excitotoxicity, disease-associated RBPs, and nucleocytoplasmic transport.

Keywords: RNA transport; amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); excitatory neurotransmission; excitotoxicity; fused in sarcoma/translocated in liposarcoma (FUS/TLS); glutamate; glutamate ionotropic receptor AMPA type subunit 2 (Gria2); glutamate receptor 2 (GluA2); neurodegeneration; nucleocytoplasmic transport.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amyotrophic Lateral Sclerosis
  • Calcium / metabolism*
  • Cell Nucleus / metabolism*
  • Cytoplasm
  • Frontotemporal Dementia
  • Glutamic Acid / adverse effects*
  • Humans
  • Mutation
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism*
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • Stress, Physiological*


  • FUS protein, human
  • RNA, Messenger
  • RNA-Binding Protein FUS
  • Receptors, AMPA
  • Glutamic Acid
  • glutamate receptor ionotropic, AMPA 2
  • Calcium