title: An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function.
abstract: Stress granules (SG) are membrane-less compartments involved in regulating mRNAs during stress. Aberrant forms of SGs have been implicated in age-related diseases, such as amyotrophic lateral sclerosis (ALS), but the molecular events triggering their formation are still unknown. Here, we find that misfolded proteins, such as ALS-linked variants of SOD1, specifically accumulate and aggregate within SGs in human cells. This decreases the dynamics of SGs, changes SG composition, and triggers an aberrant liquid-to-solid transition ofin vitroreconstituted compartments. We show that chaperone recruitment prevents the formation of aberrant SGs and promotes SG disassembly when the stress subsides. Moreover, we identify a backup system for SG clearance, which involves transport of aberrant SGs to the aggresome and their degradation by autophagy. Thus, cells employ a system of SG quality control to prevent accumulation of misfolded proteins and maintain the dynamic state of SGs, which may have relevance for ALS and related diseases.
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mateju
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Titus M
authors.initials: TM
authors.lastname: Franzmann
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Avinash
authors.initials: A
authors.lastname: Patel
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Andrii
authors.initials: A
authors.lastname: Kopach
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Edgar E
authors.initials: EE
authors.lastname: Boczek
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Shovamayee
authors.initials: S
authors.lastname: Maharana
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Hyun O
authors.initials: HO
authors.lastname: Lee
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Hyman
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany alberti@mpi-cbg.de.
authors.forename: Simon
authors.identifier: 0000-0003-4017-6505
authors.initials: S
authors.lastname: Alberti
mesh_terms: D003594:Cytoplasmic Granules / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D000072105:Superoxide Dismutase-1 / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1
keywords: SOD1; protein aggregation; protein misfolding; proteostasis; stress granules