SFB 1192
Project B3
Delineating the specific role of immunoproteasome function as a common modifier of glomerular disease progresion
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.
Publications
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Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice
Tomas NM, Dehde S, Meyer-Schwesinger C, Huang M, Hermans-Borgmeyer I, Maybaum J, Lucas R, von der Heide JL, Kretz O, Köllner SMS, Seifert L, Huber TB, Zahner G.Kidney Int. 2022 Sep
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ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage
Sachs M, Wetzel S, Reichelt J, Sachs W, Schebsdat L, Zielinski S, Seipold L, Heintz L, Müller SA, Kretz O, Lindenmeyer M, Wiech T, Huber TB, Lüllmann-Rauch R, Lichtenthaler SF, Saftig P, Meyer-Schwesinger C. J Am Soc Nephrol. 2021 Mar
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Distinct modes of balancing glomerular cell proteostasis in mucolipidosis type II and III prevent proteinuria.
Sachs W, Sachs M, Krüger E, Zielinski S, Kretz, Huber TB, Baranowsky A, Westermann LM, Volontolini Velho R, Ludwig NF, Yorgan TA, Di Lorenzo G, Kollmann K, Braulke T, Schwartz IV, Schinke T, Danyukova T, Pohl S, Meyer-Schwesinger C.J Am Soc Nephrol. 2020 Aug
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The Ubiquitin Proteasome System in Kidney Physiology and Disease.
Meyer-Schwesinger CNat Rev Nephrol. 2019 Apr
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Thrombospondin Type 1 Domain-Containing 7A (THSD7A) Localizes to the Slit Diaphragm and Stabilizes Membrane Dynamics of Fully Differentiated Podocytes.
Herwig J, Skuza S, Sachs W, Sachs M, Failla AV, Rune G, Meyer TN, Fester L, Meyer-Schwesinger CJ Am Soc Nephrol. 2019 Apr
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Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks.
Reinicke, AT, Laban, K, Sachs M, Kraus V, Walden M, Damme M, Sachs W, Reichelt J, Schweizer M, Janiesch CP, Duncan KE, Saftig P, Rischen MM, Morellini F, Meyer-Schwesinger CProc Natl Acad Sci U S A. 2019 Mar
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Protecting the kidney against autoimmunity and inflammation.
Christian Kurts, Catherine Meyer-SchwesingerNat Rev Nephrol. 2018 Dec
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Ubiquitin C-Terminal Hydrolase L1 is required for regulated protein degradation through the ubiquitin proteasome system in kidney
Radón V, Czesla M, Reichelt J, Fehlert J, Hammel A, Rosendahl A, Knop J, Wiech T, Wenzel U, Sachs M, Reinicke A, Stahl R, Meyer-Schwesinger CKidney Int. 2018 Jan
Project-Team
Project Leader
Prof. Dr. Catherine Meyer-Schwesinger
Co-Workers
Marlies Sachs
Wiebke Sachs
Sinah Skuza
Uta Wedekind