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The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration

Author

Listed:
  • Wiebke Sachs

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Lukas Blume

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Desiree Loreth

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Lisa Schebsdat

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Favian Hatje

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Sybille Koehler

    (Hamburg Center of Kidney Health
    University Medical Center Hamburg-Eppendorf)

  • Uta Wedekind

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Marlies Sachs

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Stephanie Zieliniski

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Johannes Brand

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

  • Christian Conze

    (Leibniz Institute of Virology)

  • Bogdan I. Florea

    (Leiden University)

  • Frank Heppner

    (Charité)

  • Elke Krüger

    (University Medicine Greifswald)

  • Markus M. Rinschen

    (Hamburg Center of Kidney Health
    University Medical Center Hamburg-Eppendorf)

  • Oliver Kretz

    (Hamburg Center of Kidney Health
    University Medical Center Hamburg-Eppendorf)

  • Roland Thünauer

    (Leibniz Institute of Virology
    University Hamburg
    Advanced Light and Fluorescence Microscopy (ALFM) Facility at the Centre for Structural Systems Biology (CSSB))

  • Catherine Meyer-Schwesinger

    (University Medical Center Hamburg-Eppendorf
    Hamburg Center of Kidney Health)

Abstract

Kidney filtration is ensured by the interaction of podocytes, endothelial and mesangial cells. Immunoglobulin accumulation at the filtration barrier is pathognomonic for glomerular injury. The mechanisms that regulate filter permeability are unknown. Here, we identify a pivotal role for the proteasome in a specific cell type. Combining genetic and inhibitor-based human, pig, mouse, and Drosophila models we demonstrate that the proteasome maintains filtration barrier integrity, with podocytes requiring the constitutive and glomerular endothelial cells the immunoproteasomal activity. Endothelial immunoproteasome deficiency as well as proteasome inhibition disrupt the filtration barrier in mice, resulting in pathologic immunoglobulin deposition. Mechanistically, we observe reduced endocytic activity, which leads to altered membrane recycling and endocytic receptor turnover. This work expands the concept of the (immuno)proteasome as a control protease orchestrating protein degradation and antigen presentation and endocytosis, providing new therapeutic targets to treat disease-associated glomerular protein accumulations.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46273-0
    DOI: 10.1038/s41467-024-46273-0
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    References listed on IDEAS

    as
    1. Avital Eisenberg-Lerner & Ron Benyair & Noa Hizkiahou & Neta Nudel & Roey Maor & Matthias P. Kramer & Merav D. Shmueli & Inbal Zigdon & Marina Cherniavsky Lev & Adi Ulman & Jitka Yehudith Sagiv & Moll, 2020. "Golgi organization is regulated by proteasomal degradation," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Helen Weavers & Silvia Prieto-Sánchez & Ferdinand Grawe & Amparo Garcia-López & Ruben Artero & Michaela Wilsch-Bräuninger & Mar Ruiz-Gómez & Helen Skaer & Barry Denholm, 2009. "The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm," Nature, Nature, vol. 457(7227), pages 322-326, January.
    3. Bing He & Ping Chen & Sonia Zambrano & Dina Dabaghie & Yizhou Hu & Katja Möller-Hackbarth & David Unnersjö-Jess & Gül Gizem Korkut & Emmanuelle Charrin & Marie Jeansson & Maria Bintanel-Morcillo & Ann, 2021. "Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    4. Yingdi Wang & Masanori Nakayama & Mara E. Pitulescu & Tim S. Schmidt & Magdalena L. Bochenek & Akira Sakakibara & Susanne Adams & Alice Davy & Urban Deutsch & Urs Lüthi & Alcide Barberis & Laura E. Be, 2010. "Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis," Nature, Nature, vol. 465(7297), pages 483-486, May.
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    Full references (including those not matched with items on IDEAS)

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