The prion-like domain of Fused in Sarcoma is phosphorylated by multiple kinases affecting liquid- and solid-phase transitions
| Autor: | Izzy Owen, Frank Shewmaker, Isabelle Hannula, Hala Wyne, Debra S. Yee, Kevin Gery, Meenakshi Sundrum, Shannon N Rhoads |
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| Rok vydání: | 2020 |
| Předmět: |
Proteomics
Cytoplasm Phase transition Disease mutation Prions Biology Protein Aggregation Pathological Phase Transition Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine medicine Humans Phosphorylation Prion protein Molecular Biology 030304 developmental biology Cell Nucleus 0303 health sciences Kinase Articles Cell Biology medicine.disease Cell biology Cell Biology of Disease Mutation Domain (ring theory) RNA-Binding Protein FUS Sarcoma Protein Processing Post-Translational 030217 neurology & neurosurgery DNA Damage |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| DOI: | 10.1091/mbc.e20-05-0290 |
| Popis: | Fused in Sarcoma (FUS) is a ubiquitously expressed protein that can phase-separate from nucleoplasm and cytoplasm into distinct liquid-droplet structures. It is predominantly nuclear and most of its functions are related to RNA and DNA metabolism. Excessive persistence of FUS within cytoplasmic phase-separated assemblies is implicated in the diseases amyotrophic lateral sclerosis and frontotemporal dementia. Phosphorylation of FUS's prion-like domain (PrLD) by nuclear phosphatidylinositol 3-kinase-related kinase (PIKK)-family kinases following DNA damage was previously shown to alter FUS's liquid-phase and solid-phase transitions in cell models and in vitro. However, proteomic data suggest that FUS's PrLD is phosphorylated at numerous additional sites, and it is unknown if other non-PIKK and nonnuclear kinases might be influencing FUS's phase transitions. Here we evaluate disease mutations and stress conditions that increase FUS accumulation into cytoplasmic phase-separated structures. We observed that cytoplasmic liquid-phase structures contain FUS phosphorylated at novel sites, which occurred independent of PIKK-family kinases. We engineered phosphomimetic substitutions within FUS's PrLD and observed that mimicking a few phosphorylation sites strongly inhibited FUS solid-phase aggregation, while minimally altering liquid-phase condensation. These effects occurred independent of the exact location of the phosphomimetic substitutions, suggesting that modulation of PrLD phosphorylation may offer therapeutic strategies that are specific for solid-phase aggregation observed in disease. |
| Databáze: | OpenAIRE |
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