title: Phosphorylation of C-terminal tyrosine residue 526 in FUS impairs its nuclear import.
abstract: Aberrant cytoplasmic aggregation of FUS, which is caused by mutations primarily in the C-terminal nuclear localisation signal, is associated with 3% of cases of familial amyotrophic lateral sclerosis (ALS). FUS aggregates are also pathognomonic for 10% of all frontotemporal lobar degeneration (FTLD) cases; however, these cases are not associated with mutations in the gene encoding FUS. This suggests that there are differences in the mechanisms that drive inclusion formation of FUS in ALS and FTLD. Here, we show that the C-terminal tyrosine residue at position 526 of FUS is crucial for normal nuclear import. This tyrosine is subjected to phosphorylation, which reduces interaction with transportin 1 and might consequentially affect the transport of FUS into the nucleus. Furthermore, we show that this phosphorylation can occur through the activity of the Src family of kinases. Our study implicates phosphorylation as an additional mechanism by which nuclear transport of FUS might be regulated and potentially perturbed in ALS and FTLD.
authors.affiliation: Jožef Stefan Institute, Department of Biotechnology, Jamova 39, Ljubljana 1000, Slovenia.
authors.forename: Simona
authors.initials: S
authors.lastname: Darovic
authors.affiliation: Jožef Stefan Institute, Department of Biotechnology, Jamova 39, Ljubljana 1000, Slovenia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Prpar Mihevc
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana 1000, Slovenia.
authors.forename: Vera
authors.initials: V
authors.lastname: Župunski
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana 1000, Slovenia.
authors.forename: Gregor
authors.initials: G
authors.lastname: Gunčar
authors.affiliation: Jožef Stefan Institute, Department of Biotechnology, Jamova 39, Ljubljana 1000, Slovenia.
authors.forename: Maja
authors.initials: M
authors.lastname: Štalekar
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 9RT, UK.
authors.forename: Youn-Bok
authors.initials: YB
authors.lastname: Lee
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, King's College London, London SE5 9RT, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Jožef Stefan Institute, Department of Biotechnology, Jamova 39, Ljubljana 1000, Slovenia Biomedical Research Institute BRIS, Puhova 10, Ljubljana 1000, Slovenia boris.rogelj@ijs.si.
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS; C108121:TNPO1 protein, human; D028961:beta Karyopherins; D014443:Tyrosine
keywords: Amyotrophic lateral sclerosis; FUS; Frontotemporal lobar degeneration; Nuclear import; Phosphorylation; Transportin 1