期刊
CELL REPORTS
卷 16, 期 1, 页码 222-231出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.05.076
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资金
- Spanish Ministry of Economy and Competitiveness [BFU2011-26206, BFU2014-55054-P]
- European Research Council Consolidator grant IR-DC [616434]
- European Research Council Starting Grant [Ribomylome 309545]
- Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR)
- EMBO Young Investigator Program
- EMBL-CRG Systems Biology Program
- AXA Research Fund
- FP7 Marie Curie COFUND action
- Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa [SEV-2012-0208]
- ICREA Funding Source: Custom
- European Research Council (ERC) [616434] Funding Source: European Research Council (ERC)
Multiple human diseases are associated with a liquid-to-solid phase transition resulting in the formation of amyloid fibers or protein aggregates. Here, we present an alternative mechanism for cellular toxicity based on a concentration-dependent liquid-liquid demixing. Analyzing proteins that are toxic when their concentration is increased in yeast reveals that they share physicochemical properties with proteins that participate in physiological liquid-liquid demixing in the cell. Increasing the concentration of one of these proteins indeed results in the formation of cytoplasmic foci with liquid properties. Demixing occurs at the onset of toxicity and titrates proteins and mRNAs from the cytoplasm. Focus formation is reversible, and resumption of growth occurs as the foci dissolve as protein concentration falls. Preventing demixing abolishes the dosage sensitivity of the protein. We propose that triggering inappropriate liquid phase separation may be an important cause of dosage sensitivity and a determinant of human disease.
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