The Proteasome Modulates Endocytosis in a Glomerular Cell Type Specific Modality to Secure Kidney Filtration

Abstract

Abstract Kidney filtration is ensured in the glomerulus by the interaction of podocytes, endothelial and mesangial cells. In comparison to autophagy and mitochondrial function, the proteasome system represents a completely unexplored aspect of cellular metabolism especially in kidney cells, even though it is getting more and more clear that proteasome alterations are central to many glomerular metabolic and immune pathologies. Here we identify the proteasome to be critical in a conserved cell type specific modality. Combining genetic and inhibitor-based human, pig, mouse, and Drosophila models we demonstrate that the proteasome ensures filtration barrier integrity, with podocyte metabolism depending on the constitutive proteasome whereas glomerular endothelial cells depend on the immunoproteasome. Endothelial immunoproteasome deficiency as well as proteasome inhibition disrupt the filtration barrier in mice, resulting in pathologic immunoglobulin deposition under the slit diaphragm and glomerular basement membrane alterations. Mechanistically, a reduced endocytic activity was identified, which relates to altered membrane recycling and turnover of endocytic receptors for collagen 4 and immunoglobulins. Our findings expand the concept of the (immuno)proteasome as a control protease for protein degradation and antigen presentation to an orchestrator of endocytosis and will lead to new therapeutic principles in targeting disease-associated glomerular protein accumulations.