Reference - Detail
|Author||Yamaguchi A, Takanashi K.|
|Title||FUS interacts with nuclear matrix-associated protein SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription.|
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.
|MeSH||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|
|WOS Category||BIOCHEMISTRY & MOLECULAR BIOLOGY|
|DNA material||Genome Network Project Human cDNA IRAL001I24 (HGY080616)|