FUS Regulates Activity of MicroRNA-Mediated Gene Silencing

Mol Cell. 2018 Mar 1;69(5):787-801.e8. doi: 10.1016/j.molcel.2018.02.001.


MicroRNA-mediated gene silencing is a fundamental mechanism in the regulation of gene expression. It remains unclear how the efficiency of RNA silencing could be influenced by RNA-binding proteins associated with the microRNA-induced silencing complex (miRISC). Here we report that fused in sarcoma (FUS), an RNA-binding protein linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), interacts with the core miRISC component AGO2 and is required for optimal microRNA-mediated gene silencing. FUS promotes gene silencing by binding to microRNA and mRNA targets, as illustrated by its action on miR-200c and its target ZEB1. A truncated mutant form of FUS that leads its carriers to an aggressive form of ALS, R495X, impairs microRNA-mediated gene silencing. The C. elegans homolog fust-1 also shares a conserved role in regulating the microRNA pathway. Collectively, our results suggest a role for FUS in regulating the activity of microRNA-mediated silencing.

Keywords: AGO2; ALS; Argonaute; C. elegans; FTD; FUS; RNA; gene silencing; microRNA; neurodegeneration.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Gene Silencing*
  • HEK293 Cells
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA, Helminth / genetics
  • RNA, Helminth / metabolism*
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism*


  • Caenorhabditis elegans Proteins
  • FUS protein, human
  • FUS protein, mouse
  • MIRN200 microRNA, human
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • RNA, Helminth
  • RNA-Binding Protein FUS