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

Wiebke Sachs, Lukas Blume, Desiree Loreth, Lisa Schebsdat, Favian Hatje, Sybille Koehler, Uta Wedekind, Marlies Sachs, Stephanie Zieliniski, Johannes Brand, Christian Conze, Bogdan I. Florea, Frank Heppner, Elke Krüger, Markus M. Rinschen, Oliver Kretz, Roland Thünauer and Catherine Meyer-Schwesinger ()
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Wiebke Sachs: University Medical Center Hamburg-Eppendorf
Lukas Blume: University Medical Center Hamburg-Eppendorf
Desiree Loreth: University Medical Center Hamburg-Eppendorf
Lisa Schebsdat: University Medical Center Hamburg-Eppendorf
Favian Hatje: University Medical Center Hamburg-Eppendorf
Sybille Koehler: Hamburg Center of Kidney Health
Uta Wedekind: University Medical Center Hamburg-Eppendorf
Marlies Sachs: University Medical Center Hamburg-Eppendorf
Stephanie Zieliniski: University Medical Center Hamburg-Eppendorf
Johannes Brand: University Medical Center Hamburg-Eppendorf
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
Oliver Kretz: Hamburg Center of Kidney Health
Roland Thünauer: Leibniz Institute of Virology
Catherine Meyer-Schwesinger: University Medical Center Hamburg-Eppendorf

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46273-0

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