Journal
CELL
Volume 173, Issue 3, Pages 720-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.03.056
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Funding
- Canadian Consortium on Neurodegeneration and Aging of the Canadian Institutes of Health Research
- Wellcome Trust
- European Research Council starting grant [RIBOMYLOME_ 309545]
- European Research Council [322817]
- Swiss National Foundation for Science
- ALS Society of Canada/Brain Canada
- BBSRC [BB/H023917/1] Funding Source: UKRI
- EPSRC [EP/H018301/1] Funding Source: UKRI
- MRC [G0902243, MR/K02292X/1] Funding Source: UKRI
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Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-pi interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUSassociated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular beta-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.
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