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...

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Bibliographic Details
Published in:	Scientific reports 2016-10, Vol.6 (1), p.35195-35195, Article 35195
Main Authors:	Yamaguchi, Atsushi, Takanashi, Keisuke
Format:	Article
Language:	eng
Subjects:	Alternative Splicing Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - etiology Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Androgen receptors Animals Brain - metabolism Cell Line Chromatin Chromatin - metabolism Dementia disorders Deoxyribonucleic acid DNA Frontotemporal dementia FUS protein HEK293 Cells Humans Ligands Localization 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 Nuclei Pathogenesis Protein Aggregation, Pathological - genetics Protein Aggregation, Pathological - metabolism Protein Interaction Domains and Motifs Proteins Receptors, Estrogen - chemistry Receptors, Estrogen - genetics Receptors, Estrogen - metabolism Ribonucleic acid RNA RNA-binding protein 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 SAP protein Sarcoma Spinal Cord - metabolism Splicing Transcription Transcription, Genetic Two-Hybrid System Techniques
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Summary:	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.
ISSN:	2045-2322 2045-2322