Mutations disrupting the C-terminal nuclear localisation signal of fused in sarcoma (FUS) are found in 3% of familial amyotrophic lateral sclerosis cases (ALS); these have cytoplasmic FUS inclusions that are likely to result from a disruption of its nuclear import by transportin 1 (TNPO1). FUS inclusions are also found in frontotemporal lobar degeneration (FTLD), although no FUS mutations have been associated with this disease, suggesting the existence of another mechanism that regulates nuclear import of FUS. Here (p. ), Boris Rogelj and colleagues discover that phosphorylation of the tyrosine residue at position 526 (Y526) in the C-terminus of FUS could underlie the difference in the mechanisms of aggregation between ALS and FTLD. They show that deletion or substitution of Y526 by phosphomimetic glutamate disrupts the interaction of FUS with TNPO1 and results in its cytoplasmic localisation. By contrast, substitution of Y526 with phenylalanine retains the FUS-TNPO1 interaction and, subsequently, FUS is imported into the nucleus within most cells. Because the authors find endogenous FUS to be tyrosine-phosphorylated, they use a truncated peptide to demonstrate that phospho-Y526 FUS can no longer bind to TNPO1. Furthermore, their data suggest that phosphorylation of Y526 is mediated by a Src kinase because phosphorylation at Y526 is decreased in the presence of a Src-family inhibitor. Thus, this study significantly contributes not only to our understanding of FUS biology, but also to its role in the molecular pathology of ALS and FTLD.
