TY  - JOUR
AU  - Sachs, Wiebke
AU  - Blume, Lukas
AU  - Loreth, Desiree
AU  - Schebsdat, Lisa
AU  - Hatje, Favian
AU  - Koehler, Sybille
AU  - Wedekind, Uta
AU  - Sachs, Marlies
AU  - Zieliniski, Stephanie
AU  - Brand, Johannes
AU  - Conze, Christian
AU  - Florea, Bogdan I.
AU  - Heppner, Frank
AU  - Krüger, Elke
AU  - Rinschen, Markus M.
AU  - Kretz, Oliver
AU  - Thünauer, Roland
AU  - Meyer-Schwesinger, Catherine
TI  - The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - PUBDB-2024-05766
SP  - 1897
PY  - 2024
N1  - DFG Research Infrastructure Portal: RI_00489 for excellent technical assistance
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:38429282
UR  - <Go to ISI:>//WOS:001447479900019
DO  - DOI:10.1038/s41467-024-46273-0
UR  - https://bib-pubdb1.desy.de/record/614226
ER  -