title: The effect of PRMT1-mediated arginine methylation on the subcellular localization, stress granules, and detergent-insoluble aggregates of FUS/TLS.
abstract: Fused in sarcoma/translocated in liposarcoma (FUS/TLS) is one of causative genes for familial amyotrophic lateral sclerosis (ALS). In order to identify binding partners for FUS/TLS, we performed a yeast two-hybrid screening and found that protein arginine methyltransferase 1 (PRMT1) is one of binding partners primarily in the nucleus. In vitro and in vivo methylation assays showed that FUS/TLS could be methylated by PRMT1. The modulation of arginine methylation levels by a general methyltransferase inhibitor or conditional over-expression of PRMT1 altered slightly the nucleus-cytoplasmic ratio of FUS/TLS in cell fractionation assays. Although co-localized primarily in the nucleus in normal condition, FUS/TLS and PRMT1 were partially recruited to the cytoplasmic granules under oxidative stress, which were merged with stress granules (SGs) markers in SH-SY5Y cell. C-terminal truncated form of FUS/TLS (FUS-dC), which lacks C-terminal nuclear localization signal (NLS), formed cytoplasmic inclusions like ALS-linked FUS mutants and was partially co-localized with PRMT1. Furthermore, conditional over-expression of PRMT1 reduced the FUS-dC-mediated SGs formation and the detergent-insoluble aggregates in HEK293 cells. These findings indicate that PRMT1-mediated arginine methylation could be implicated in the nucleus-cytoplasmic shuttling of FUS/TLS and in the SGs formation and the detergent-insoluble inclusions of ALS-linked FUS/TLS mutants.
authors.affiliation: Department of Neurobiology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Kitajo
mesh_terms: D001120:Arginine / Q000378:metabolism*; D018053:Arsenites / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D003902:Detergents; D057809:HEK293 Cells; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000187:drug effects; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000737:chemistry* / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D012995:Solubility; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D018053:Arsenites; D003902:Detergents; D034702:RNA-Binding Protein FUS; D012097:Repressor Proteins; D001120:Arginine; C099988:PRMT1 protein, human; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; C015001:arsenite