FUS interacts with nuclear matrix-associated protein SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription

Sci Rep. 2016 Oct 12:6:35195. doi: 10.1038/srep35195.

Abstract

FUS (Fused-in-Sarcoma) is a multifunctional DNA/RNA binding protein linked to familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Since FUS is localized mainly in the nucleus with nucleo-cytoplasmic shuttling, it is critical to understand physiological functions in the nucleus to clarify pathogenesis. Here we report a yeast two-hybrid screening identified FUS interaction with nuclear matrix-associated protein SAFB1 (scaffold attachment factor B1). FUS and SAFB1, abundant in chromatin-bound fraction, interact in a DNA-dependent manner. N-terminal SAP domain of SAFB1, a DNA-binding motif, was required for its localization to chromatin-bound fraction and splicing regulation. In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. FUS and SAFB1 also interact with Androgen Receptor (AR) regulating ligand-dependent transcription. Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. These findings indicate SAFB1 could be a FUS's functional platform in chromatin compartment to regulate RNA splicing and ligand-dependent transcription and shed light on the etiological significance of nuclear matrix-associated proteins in ALS pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Brain / metabolism
  • Cell Line
  • Chromatin / metabolism
  • HEK293 Cells
  • Humans
  • Ligands
  • Male
  • Matrix Attachment Region Binding Proteins / chemistry
  • Matrix Attachment Region Binding Proteins / genetics
  • Matrix Attachment Region Binding Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Nuclear Matrix / metabolism
  • Nuclear Matrix-Associated Proteins / chemistry
  • Nuclear Matrix-Associated Proteins / genetics
  • Nuclear Matrix-Associated Proteins / metabolism*
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Interaction Domains and Motifs
  • RNA-Binding Protein FUS / chemistry
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Spinal Cord / metabolism
  • Transcription, Genetic
  • Two-Hybrid System Techniques

Substances

  • Chromatin
  • FUS protein, human
  • Ligands
  • MATR3 protein, human
  • Matrix Attachment Region Binding Proteins
  • Mutant Proteins
  • Nuclear Matrix-Associated Proteins
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins
  • Receptors, Estrogen
  • SAFB protein, human

Supplementary concepts

  • Amyotrophic lateral sclerosis 1