The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration
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The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration. / 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.
In: NAT COMMUN, Vol. 15, No. 1, 01.03.2024, p. 1897.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration
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
N1 - © 2024. The Author(s).
PY - 2024/3/1
Y1 - 2024/3/1
N2 - 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.
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.
KW - Mice
KW - Humans
KW - Animals
KW - Swine
KW - Proteasome Endopeptidase Complex
KW - Endothelial Cells
KW - Kidney Glomerulus/pathology
KW - Kidney Diseases/pathology
KW - Endocytosis
KW - Immunoglobulins
U2 - 10.1038/s41467-024-46273-0
DO - 10.1038/s41467-024-46273-0
M3 - SCORING: Journal article
C2 - 38429282
VL - 15
SP - 1897
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -