| Autor: |
Sachs, Wiebke, Blume, Lukas, Loreth, Desiree, Schebsdat, Lisa, Hatje, Favian, Koehler, Sybille, Wedekind, Uta, Sachs, Marlies, Zieliniski, Stephanie, Brand, Johannes, Conze, Christian, Florea, Bogdan I., Heppner, Frank, Krüger, Elke, Rinschen, Markus M., Kretz, Oliver, Thünauer, Roland, Meyer-Schwesinger, Catherine |
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| Zdroj: |
Nature Communications; 3/4/2024, Vol. 15 Issue 1, p1-21, 21p |
| Abstrakt: |
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. In the kidney, maintaining permeability of the filtration barrier is critical. Here, Sachs W. et al show that homeostasis of podocytes and glomerular endothelial cells relies on differing proteasome constitutions which orchestrate endocytic activity in addition to protein degradation. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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