Journal Article

PUBDB-2024-05766

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration

Sachs, W. ; Blume, L. ; Loreth, D. ; Schebsdat, L. ; Hatje, F. ; Koehler, S. ; Wedekind, U. ; Sachs, M. ; Zieliniski, S. ; Brand, J. ; Conze, C. ; Florea, B. I. ; Heppner, F. ; Krüger, E. ; Rinschen, M. M. ; Kretz, O. ; Thünauer, R.Extern*CSSB* ; Meyer-Schwesinger, C. (Corresponding author)

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-46273-0  doi:10.3204/PUBDB-2024-05766

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.

Note: DFG Research Infrastructure Portal: RI_00489 for excellent technical assistance

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Contributing Institute(s):

1. CSSB-CF-ALFM (CSSB-CF-ALFM)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Experiment(s):

1. (Advanced Light and Fluorescence Microscopy Facility)

Appears in the scientific report 2024

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