A Concentration-Dependent Liquid Phase Separation Can Cause Toxicity upon Increased Protein Expression.
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.
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Benedetta
B
Bolognesi
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Nieves
N
Lorenzo Gotor
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Riddhiman
R
Dhar
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Davide
D
Cirillo
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
Marta
M
Baldrighi
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain. Electronic address: gian.tartaglia@crg.eu.
Gian Gaetano
GG
Tartaglia
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain. Electronic address: ben.lehner@crg.eu.
Ben
B
Lehner
D003593:Cytoplasm / Q000378:metabolism; D018628:Gene Dosage; D044367:Phase Transition; D014176:Protein Biosynthesis; D000072417:Protein Domains; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000633:toxicity*
D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins