The Proteasome Modulates Endocytosis in a Glomerular Cell Type Specific Modality to Secure Kidney Filtration

Research Square

Abstract

Abstract Kidney filtration is ensured in the glomerulus by the interaction of podocytes, endothelial and mesangial cells. In comparison to autophagy and mitochondrial function, the proteasome system represents a completely unexplored aspect of cellular metabolism especially in kidney cells, even though it is getting more and more clear that proteasome alterations are central to many glomerular metabolic and immune pathologies. Here we identify the proteasome to be critical in a conserved cell type specific modality. Combining genetic and inhibitor-based human, pig, mouse, and Drosophila models we demonstrate that the proteasome ensures filtration barrier integrity, with podocyte metabolism depending on the constitutive proteasome whereas glomerular endothelial cells depend on the immunoproteasome. Endothelial immunoproteasome deficiency as well as proteasome inhibition disrupt the filtration barrier in mice, resulting in pathologic immunoglobulin deposition under the slit diaphragm and glomerular basement membrane alterations. Mechanistically, a reduced endocytic activity was identified, which relates to altered membrane recycling and turnover of endocytic receptors for collagen 4 and immunoglobulins. Our findings expand the concept of the (immuno)proteasome as a control protease for protein degradation and antigen presentation to an orchestrator of endocytosis and will lead to new therapeutic principles in targeting disease-associated glomerular protein accumulations.

Authors 18

1. Wiebke Sachs
   Affiliation as printed

   Institute of Cellular and Integrative Physiology

2. Lukas Blume
   Affiliation as printed

   Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

3. Desirée Loreth
   Affiliation as printed

   Institute of Cellular and Integrative Physiology

4. Lisa Schebsdat
   Affiliation as printed

   Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

5. Favian A. Hatje
   Affiliation as printed

   Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

6. Sybille Köhler

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   Nephrology, III Medical Clinic, Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg Germany

7. Uta Wedekind
   Affiliation as printed

   Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

8. Marlies Sachs
   Affiliation as printed

   Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

9. Stephanie Zielinski
   Affiliation as printed

   Institue of Cellular and Integrative Physiology

10. Johannes Brand
    Affiliation as printed

    Instiitute of Cellular and Integrative Physiology

11. Christian Conze

    Leibniz Institute of Virology (LIV)

    Affiliation as printed

    Leibniz Institute of Virology, Hamburg, Germany

12. Bogdan I. Florea Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry, Leiden University

13. Frank L. Heppner

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Institute of Neuropathology, Charité, Berlin, Germany

14. Elke Krüger

    Universitätsmedizin Greifswald · Universität Greifswald

    Affiliation as printed

    Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Germany

15. Markus Matthias Rinschen

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Nephrology, III Medical Clinic, Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg Germany

16. Oliver Kretz

    Universität Hamburg · University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    University Medical Center Hamburg-Eppendorf

    Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

    Nephrology, III Medical Clinic, Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg Germany

    Technology Platform Light Microscopy (TPLM), University Hamburg, Germany

17. Roland Thünauer

    Universität Hamburg · University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Technology Platform Light Microscopy (TPLM), University Hamburg, Germany

    Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

    Nephrology, III Medical Clinic, Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg Germany

    University Medical Center Hamburg-Eppendorf

18. Catherine Meyer‐Schwesinger corresponding

    Universität Hamburg · University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Cellular and Integrative Physiology, Center for Experimental Medicine

    Nephrology, III Medical Clinic, Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg Germany

    Technology Platform Light Microscopy (TPLM), University Hamburg, Germany

    University Medical Center Hamburg-Eppendorf