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Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis

Author

Listed:
  • Julia Reichelt

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Wiebke Sachs

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Sarah Frömbling

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Julia Fehlert

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Maja Studencka-Turski

    (Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald)

  • Anna Betz

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Desiree Loreth

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Lukas Blume

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Susanne Witt

    (Protein production Core Facility, Centre for Structural Systems Biology, Deutsches Elektronen-Synchrotron DESY)

  • Sandra Pohl

    (University Medical Center Hamburg-Eppendorf)

  • Johannes Brand

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Maire Czesla

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Jan Knop

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Bogdan I. Florea

    (Bio-organic synthesis group, Leiden University)

  • Stephanie Zielinski

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Marlies Sachs

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

  • Elion Hoxha

    (III Medical Clinic and Polyclinic, Nephrology, University Medical Center Hamburg-Eppendorf)

  • Irm Hermans-Borgmeyer

    (Transgenic Animal Service Group, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf)

  • Gunther Zahner

    (III Medical Clinic and Polyclinic, Nephrology, University Medical Center Hamburg-Eppendorf)

  • Thorsten Wiech

    (Institute of Pathology, Nephropathology Section, University Medical Center Hamburg-Eppendorf)

  • Elke Krüger

    (Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald)

  • Catherine Meyer-Schwesinger

    (Institute of Cellular and Integrative Physiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf)

Abstract

Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1.

Suggested Citation

  • Julia Reichelt & Wiebke Sachs & Sarah Frömbling & Julia Fehlert & Maja Studencka-Turski & Anna Betz & Desiree Loreth & Lukas Blume & Susanne Witt & Sandra Pohl & Johannes Brand & Maire Czesla & Jan Kn, 2023. "Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37836-8
    DOI: 10.1038/s41467-023-37836-8
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    References listed on IDEAS

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    1. Indrajit Sahu & Sachitanand M. Mali & Prasad Sulkshane & Cong Xu & Andrey Rozenberg & Roni Morag & Manisha Priyadarsini Sahoo & Sumeet K. Singh & Zhanyu Ding & Yifan Wang & Sharleen Day & Yao Cong & O, 2021. "The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
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    Cited by:

    1. Wiebke Sachs & Lukas Blume & Desiree Loreth & Lisa Schebsdat & Favian Hatje & Sybille Koehler & Uta Wedekind & Marlies Sachs & Stephanie Zieliniski & Johannes Brand & Christian Conze & Bogdan I. Flore, 2024. "The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Wenquan Liang & Ru Feng & Xiaojia Li & Xingwei Duan & Shourui Feng & Jun Chen & Yicheng Li & Junqi Chen & Zezheng Liu & Xiaogang Wang & Guangfeng Ruan & Su’an Tang & Changhai Ding & Bin Huang & Zhipen, 2024. "A RANKL-UCHL1-sCD13 negative feedback loop limits osteoclastogenesis in subchondral bone to prevent osteoarthritis progression," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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