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000614226 245__ $$aThe proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration
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000614226 520__ $$aKidney 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.
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000614226 7001_ $$00000-0003-1889-0470$$aBlume, Lukas$$b1
000614226 7001_ $$00000-0003-0827-149X$$aLoreth, Desiree$$b2
000614226 7001_ $$aSchebsdat, Lisa$$b3
000614226 7001_ $$aHatje, Favian$$b4
000614226 7001_ $$aKoehler, Sybille$$b5
000614226 7001_ $$aWedekind, Uta$$b6
000614226 7001_ $$aSachs, Marlies$$b7
000614226 7001_ $$aZieliniski, Stephanie$$b8
000614226 7001_ $$aBrand, Johannes$$b9
000614226 7001_ $$00000-0002-8849-1064$$aConze, Christian$$b10
000614226 7001_ $$00000-0001-7114-2266$$aFlorea, Bogdan I.$$b11
000614226 7001_ $$00000-0001-9816-8917$$aHeppner, Frank$$b12
000614226 7001_ $$00000-0002-2551-242X$$aKrüger, Elke$$b13
000614226 7001_ $$00000-0002-9252-1342$$aRinschen, Markus M.$$b14
000614226 7001_ $$aKretz, Oliver$$b15
000614226 7001_ $$0P:(DE-H253)PIP1087856$$aThünauer, Roland$$b16
000614226 7001_ $$0P:(DE-HGF)0$$aMeyer-Schwesinger, Catherine$$b17$$eCorresponding author
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