Proteostasis regulates cell maintenance, stress resistance and function. Previously we discovered that defective protein turnover associated with irreversible glomerular disease in humans and rodents. Particularly, podocytes and endothelial cells strongly depended on an intact ubiquitin proteasome system (UPS) with global proteasome inhibition resulting in proteinuria and abnormal glomerular protein accumulation. Furthermore, we demonstrated that the deubiquitinase UCH-L1 was highly enriched in injured podocytes and regulated proteasomal abundance and function, thereby affecting the course of disease. Representing another specific component of the UPS, we also found the immunoproteasome, a proteolytic distinct form of the proteasome, to be present in injured podocytes. However, in contrast to the global inhibition of the proteasome, deficiency of the immunoproteasome did not aggravate but attenuate podocyte injury in glomerulonephritis (GN). Thus, we hypothesize that these different mechanisms of protein degradation act in multiple roles to maintain podocyte homeostasis and that the understanding of proteasome action will allow to precisely map and potentially interfere with the progression of glomerular diseases. Therefore, the overall goal of this study is a detailed functional analysis of the UPS and there specifically of the immunoproteasome, which will be addressed by the following aims: 1) Assessment of the cell-specific therapeutic potential of immunoproteasome inhibition in GN. 2) Mechanistic understanding of the functional consequences of immunoproteasomal degradation for glomerular cells in GN. 3) Evaluation of the activity status of UPS players as indicators of progressive podocyte injury. Collectively, our results will offer insights into the novel scheme of UPS and proteostasis-mediated glomerular disease as a prerequisite for potential new therapeutic approaches in GN.
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