Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent and RNA-independent mechanisms.
Fused in sarcoma (FUS) is an RNA-binding protein involved in pathogenesis of several neurodegenerative diseases. Aggregation of mislocalized FUS into non-amyloid inclusions is believed to be pivotal in the development of cell dysfunction, but the mechanism of their formation is unclear. Using transient expression of a panel of deletion and chimeric FUS variants in various cultured cells, we demonstrated that FUS accumulating in the cytoplasm nucleates a novel type of RNA granules, FUS granules (FGs), that are structurally similar but not identical to physiological RNA transport granules. Formation of FGs requires FUS N-terminal prion-like domain and the ability to bind specific RNAs. Clustering of FGs coupled with further recruitment of RNA and proteins produce larger structures, FUS aggregates (FAs), that resemble but are clearly distinct from stress granules. In conditions of attenuated transcription, FAs lose RNA and dissociate into RNA-free FUS complexes that become precursors of large aggresome-like structures. We propose a model of multistep FUS aggregation involving RNA-dependent and RNA-independent stages. This model can be extrapolated to formation of pathological inclusions in human FUSopathies.
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK, Institute of Physiologically Active Compounds Russian Academy of Sciences, 1 Severniy proezd, Chernogolovka 142432, Moscow Region, Russian Federation and shelkovnikovat@cardiff.ac.uk buchmanvl@cf.ac.uk.
Tatyana A
TA
Shelkovnikova
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
Hannah K
HK
Robinson
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
Joshua A
JA
Southcombe
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK, Institute of General Pathology and Pathophysiology of Russian Academy of Medical Science, 8 Baltijskaya str, Moscow 125315, Russian Federation.
Natalia
N
Ninkina
School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK, shelkovnikovat@cardiff.ac.uk buchmanvl@cf.ac.uk.
Vladimir L
VL
Buchman
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D012313:RNA / Q000235:genetics* / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D034702:RNA-Binding Protein FUS; D012313:RNA