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Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

Author

Listed:
  • Melanie Meister-Broekema

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems)

  • Rebecca Freilich

    (Institute for Neurodegenerative Disease, University of California at San Francisco)

  • Chandhuru Jagadeesan

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
    Max Planck Institute of Biochemistry)

  • Jennifer N. Rauch

    (Institute for Neurodegenerative Disease, University of California at San Francisco)

  • Rocio Bengoechea

    (Washington University School of Medicine)

  • William W. Motley

    (Johns Hopkins School of Medicine)

  • E. F. Elsiena Kuiper

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems)

  • Melania Minoia

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems)

  • Gabriel V. Furtado

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
    Universidade Federal do Rio Grande do SulPorto Alegre)

  • Maria A. W. H. Waarde

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems)

  • Shawn J. Bird

    (University of Pennsylvania)

  • Adriana Rebelo

    (University of Miami)

  • Stephan Zuchner

    (University of Miami)

  • Peter Pytel

    (University of Chicago Pritzker School of Medicine)

  • Steven S. Scherer

    (University of Pennsylvania)

  • Federica F. Morelli

    (University of Modena and Reggio Emilia Modena)

  • Serena Carra

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems
    University of Modena and Reggio Emilia Modena)

  • Conrad C. Weihl

    (Washington University School of Medicine)

  • Steven Bergink

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems)

  • Jason E. Gestwicki

    (Institute for Neurodegenerative Disease, University of California at San Francisco)

  • Harm H. Kampinga

    (University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems)

Abstract

BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery.

Suggested Citation

  • Melanie Meister-Broekema & Rebecca Freilich & Chandhuru Jagadeesan & Jennifer N. Rauch & Rocio Bengoechea & William W. Motley & E. F. Elsiena Kuiper & Melania Minoia & Gabriel V. Furtado & Maria A. W., 2018. "Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07718-5
    DOI: 10.1038/s41467-018-07718-5
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    Cited by:

    1. Antonia Vogel & Renato Arnese & Ricardo M. Gudino Carrillo & Daria Sehr & Luiza Deszcz & Andrzej Bylicki & Anton Meinhart & Tim Clausen, 2024. "UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Meital Abayev-Avraham & Yehuda Salzberg & Dar Gliksberg & Meital Oren-Suissa & Rina Rosenzweig, 2023. "DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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