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SFB 1192

Project B3

The (immuno)proteasome as a modifier of podocyte membrane dynamics in membranous nephrophathy

The connection of defective protein turnover and irreversible podocyte disease is conserved among species. We could show that the proteasome system orchestrates proteostasis and endocytosis of healthy podocytes. Upon autoimmune injury, the turnover of the membranous nephropathy (MN) antigen THSD7A is altered in a proteasome-dependent manner. In this setting we identified an injury-related hotspot of immunoproteasomal degradation at footprocesses, which modifies podocyte protein abundance and ectosome formation. Hence, we hypothesize that the proteasome system is a common modifier of podocyte disease progression, severity, and outcome. The overall goal of this project is to unravel the functional role of the (immuno)proteasome at footprocesses in MN. We will characterize 1) the mechanisms connecting the proteasome system with podocyte plasma membrane dynamics using Drosophila melanogaster; 2) the pathomechanistic function of immunoproteasomal degradation for footprocess proteostasis and remodeling in experimental mammalian models of MN and 3) the potential of glomerular and urinary MN-associated ectosomes in the prediction of MN severity and outcome. Collectively, our results will demonstrate, if the immunoproteasome-dependent formation of MN-associated ectosomes in podocytes represents a general pathophysiologic concept with therapeutic and prognostic value in membranous nephropathy.

Publications

  • 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

  • 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

  • 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

  • The Ubiquitin Proteasome System in Kidney Physiology and Disease.

    Meyer-Schwesinger CNat Rev Nephrol. 2019 Apr

  • 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

  • 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

  • Protecting the kidney against autoimmunity and inflammation.

    Christian Kurts, Catherine Meyer-SchwesingerNat Rev Nephrol. 2018 Dec

  • 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