HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain
Edgar E Boczek,
Julius Fürsch,
Marie Laura Niedermeier,
Louise Jawerth,
Marcus Jahnel,
Martine Ruer-Gruß,
Kai-Michael Kammer,
Peter Heid,
Laura Mediani,
Jie Wang,
Xiao Yan,
Andrej Pozniakovski,
Ina Poser,
Daniel Mateju,
Lars Hubatsch,
Serena Carra,
Simon Alberti,
Anthony A Hyman,
Florian Stengel
Affiliations
Edgar E Boczek
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Dewpoint Therapeutics GmbH, Dresden, Germany
Julius Fürsch
University of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
Marie Laura Niedermeier
University of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
Louise Jawerth
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
Marcus Jahnel
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Biotechnology Center, Technische Universität Dresden, Dresden, Germany
Martine Ruer-Gruß
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Kai-Michael Kammer
University of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
Peter Heid
University of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
Laura Mediani
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
Jie Wang
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Xiao Yan
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Andrej Pozniakovski
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Ina Poser
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Dewpoint Therapeutics GmbH, Dresden, Germany
Daniel Mateju
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
Serena Carra
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
Simon Alberti
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Biotechnology Center, Technische Universität Dresden, Dresden, Germany
Anthony A Hyman
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Center for Systems Biology Dresden (CSBD), Dresden, Germany
Aberrant liquid-to-solid phase transitions of biomolecular condensates have been linked to various neurodegenerative diseases. However, the underlying molecular interactions that drive aging remain enigmatic. Here, we develop quantitative time-resolved crosslinking mass spectrometry to monitor protein interactions and dynamics inside condensates formed by the protein fused in sarcoma (FUS). We identify misfolding of the RNA recognition motif of FUS as a key driver of condensate aging. We demonstrate that the small heat shock protein HspB8 partitions into FUS condensates via its intrinsically disordered domain and prevents condensate hardening via condensate-specific interactions that are mediated by its α-crystallin domain (αCD). These αCD-mediated interactions are altered in a disease-associated mutant of HspB8, which abrogates the ability of HspB8 to prevent condensate hardening. We propose that stabilizing aggregation-prone folded RNA-binding domains inside condensates by molecular chaperones may be a general mechanism to prevent aberrant phase transitions.
