A Concentration-Dependent Liquid Phase Separation Can Cause Toxicity upon Increased Protein Expression
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- dc.contributor.author Bolognesi, Benedettaca
- dc.contributor.author Lorenzo Gotor, Maria de las Nievesca
- dc.contributor.author Dhar, Riddhimanca
- dc.contributor.author Cirillo, Davideca
- dc.contributor.author Baldrighi, Martaca
- dc.contributor.author Gaetano Tartaglia, Gianca
- dc.contributor.author Lehner, Ben, 1978-ca
- dc.date.accessioned 2017-01-13T08:23:02Z
- dc.date.available 2017-01-13T08:23:02Z
- dc.date.issued 2016ca
- dc.description.abstract 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.
- dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2011-26206 and BFU2014-55054-P), a European Research Council Consolidator grant IR-DC (616434), a European Research Council Starting Grant (Ribomylome 309545), Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR), the EMBO Young Investigator Program, the EMBL-CRG Systems Biology Program, the AXA Research Fund, and by the FP7 Marie Curie COFUND action.
- dc.format.mimetype application/pdfca
- dc.identifier.citation Bolognesi B, Lorenzo Gotor MN, Dhar R, Cirillo D, Baldrighi M, Gaetano Tartaglia G, Lehner B. A Concentration-Dependent Liquid Phase Separation Can Cause Toxicity upon Increased Protein Expression. Cell Reports. 2016; 16(1): 222-231. DOI: 10.1016/j.celrep.2016.05.076ca
- dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2016.05.076
- dc.identifier.issn 2211-1247ca
- dc.identifier.uri http://hdl.handle.net/10230/27883
- dc.language.iso engca
- dc.publisher Elsevierca
- dc.relation.ispartof Cell Reports. 2016; 16(1): 222-231
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-55054-P
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
- dc.rights © 2016 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).ca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
- dc.subject.other Proteòmica
- dc.subject.other Proteïnes
- dc.title A Concentration-Dependent Liquid Phase Separation Can Cause Toxicity upon Increased Protein Expressionca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca