HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain

  1. Edgar E Boczek
  2. Julius Fürsch
  3. Marie Laura Niedermeier
  4. Louise Jawerth
  5. Marcus Jahnel
  6. Martine Ruer-Gruß
  7. Kai-Michael Kammer
  8. Peter Heid
  9. Laura Mediani
  10. Jie Wang
  11. Xiao Yan
  12. Andrej Pozniakovski
  13. Ina Poser
  14. Daniel Mateju
  15. Lars Hubatsch
  16. Serena Carra
  17. Dr. Simon Alberti
  18. Anthony A Hyman
  19. Florian Stengel  Is a corresponding author
  1. Max Planck Institute of Molecular Cell Biology and Genetics, Germany
  2. University of Konstanz, Germany
  3. Max Planck Institute for the Physics of Complex Systems, Germany
  4. Biotec, TU Dresden, Germany
  5. University of Modena and Reggio Emilia, Italy

Abstract

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 (RRM) of FUS as a key driver of condensate ageing. 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.

Data availability

All data generated or analysed during this study are included in this published article (and its supplementary information files). The MS data (raw files, xQuest, xTract and in-house quantitation output files) have been deposited to the ProteomeXchange Consortium via the PRIDE (60) partner repository with the dataset identifier PXD021114 (Username: reviewer33076@ebi.ac.uk; Password: 5atfkbP8) and PXD021115 (Username: reviewer54149@ebi.ac.uk; Password: UZW7Gnr5).

The following data sets were generated

Article and author information

Author details

  1. Edgar E Boczek

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    Edgar E Boczek, is currently an employee of Dewpoint Therapeutics..
  2. Julius Fürsch

    Department of Biology, University of Konstanz, Konstanz, Germany
    Competing interests
    No competing interests declared.
  3. Marie Laura Niedermeier

    Department of Biology, University of Konstanz, Konstanz, Germany
    Competing interests
    No competing interests declared.
  4. Louise Jawerth

    Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
    Competing interests
    No competing interests declared.
  5. Marcus Jahnel

    Biophysics, Biotec, TU Dresden, Dresden, Germany
    Competing interests
    No competing interests declared.
  6. Martine Ruer-Gruß

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    No competing interests declared.
  7. Kai-Michael Kammer

    Department of Biology, University of Konstanz, Konstanz, Germany
    Competing interests
    No competing interests declared.
  8. Peter Heid

    Department of Biology, University of Konstanz, Konstanz, Germany
    Competing interests
    No competing interests declared.
  9. Laura Mediani

    University of Modena and Reggio Emilia, Modena, Italy
    Competing interests
    No competing interests declared.
  10. Jie Wang

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    No competing interests declared.
  11. Xiao Yan

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    No competing interests declared.
  12. Andrej Pozniakovski

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    No competing interests declared.
  13. Ina Poser

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    Ina Poser, is currently an employee of Dewpoint Therapeutics.
  14. Daniel Mateju

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    No competing interests declared.
  15. Lars Hubatsch

    Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1934-7437
  16. Serena Carra

    University of Modena and Reggio Emilia, Modena, Italy
    Competing interests
    No competing interests declared.
  17. Dr. Simon Alberti

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    Dr. Simon Alberti, is a shareholder, consultant and member of the scientific advisory board for Dewpoint Therapeutics..
  18. Anthony A Hyman

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    Anthony A Hyman, is cofounder, shareholder, consultant and member of the scientific advisory board for Dewpoint Therapeutics..
  19. Florian Stengel

    Department of Biology, University of Konstanz, Konstanz, Germany
    For correspondence
    Florian.Stengel@uni-konstanz.de
    Competing interests
    Florian Stengel, is a consultant and member of the scientific advisory board for Dewpoint Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1447-4509

Funding

Deutsche Forschungsgemeinschaft (STE 2517/1-1)

  • Florian Stengel

Konstanz Research School Chemical Biology (Chemicals and small Equipment Purchase)

  • Florian Stengel

Deutsche Forschungsgemeinschaft (Cluster of Excellence Physics of Life"")

  • Dr. Simon Alberti

Deutsche Forschungsgemeinschaft (Cluster of Excellence Physics of Life"")

  • Anthony A Hyman

EU Joint Programme – Neurodegenerative Disease Research (Neurodegenerative Disease Research (JPND))

  • Serena Carra

EU Joint Programme – Neurodegenerative Disease Research (Neurodegenerative Disease Research (JPND))

  • Dr. Simon Alberti

AriSLA Foundation (Granulopathy and MLOpathy)

  • Serena Carra

MAECI (Dissolve_ALS)

  • Serena Carra

MIUR (E91I18001480001)

  • Serena Carra

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Volker Dötsch, Goethe University, Germany

Version history

  1. Preprint posted: April 13, 2021 (view preprint)
  2. Received: April 13, 2021
  3. Accepted: August 27, 2021
  4. Accepted Manuscript published: September 6, 2021 (version 1)
  5. Version of Record published: October 12, 2021 (version 2)

Copyright

© 2021, Boczek et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Edgar E Boczek
  2. Julius Fürsch
  3. Marie Laura Niedermeier
  4. Louise Jawerth
  5. Marcus Jahnel
  6. Martine Ruer-Gruß
  7. Kai-Michael Kammer
  8. Peter Heid
  9. Laura Mediani
  10. Jie Wang
  11. Xiao Yan
  12. Andrej Pozniakovski
  13. Ina Poser
  14. Daniel Mateju
  15. Lars Hubatsch
  16. Serena Carra
  17. Dr. Simon Alberti
  18. Anthony A Hyman
  19. Florian Stengel
(2021)
HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain
eLife 10:e69377.
https://doi.org/10.7554/eLife.69377

Share this article

https://doi.org/10.7554/eLife.69377

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