FUS Regulates Activity of MicroRNA-Mediated Gene Silencing

Tao Zhang, Yen Ching Wu, Patrick Mullane, Yon Ju Ji, Honghe Liu, Lu He, Amit Arora, Ho Yon Hwang, Amelia F. Alessi, Amirhossein G. Niaki, Goran Periz, Lin Guo, Hejia Wang, Elad Elkayam, Leemor Joshua-Tor, Sua Myong, John K. Kim, James Shorter, Shao En Ong, Anthony K.L. LeungJiou Wang

Research output: Contribution to journalArticle

Abstract

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. Zhang et al. find that the RNA-binding protein FUS is required for miRNA-mediated gene silencing. FUS interacts with Argonaute, microRNAs, and target transcripts, promoting interactions that lead to gene silencing.

Original languageEnglish (US)
Pages (from-to)787-801.e8
JournalMolecular cell
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2018

Keywords

  • AGO2
  • ALS
  • Argonaute
  • C. elegans
  • FTD
  • FUS
  • RNA
  • gene silencing
  • microRNA
  • neurodegeneration

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Zhang, T., Wu, Y. C., Mullane, P., Ji, Y. J., Liu, H., He, L., Arora, A., Hwang, H. Y., Alessi, A. F., Niaki, A. G., Periz, G., Guo, L., Wang, H., Elkayam, E., Joshua-Tor, L., Myong, S., Kim, J. K., Shorter, J., Ong, S. E., ... Wang, J. (2018). FUS Regulates Activity of MicroRNA-Mediated Gene Silencing. Molecular cell, 69(5), 787-801.e8. https://doi.org/10.1016/j.molcel.2018.02.001