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SFB 1192

Project B2

Structural and functional resolution of the membranous nephropathy antigens THSD7A and PLA2R1

The discoveries of phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domaincontaining 7A (THSD7A) as autoantigens in patients with membranous nephropathy (MN) have revolutionized both the diagnosis and monitoring of affected patients and the pathophysiologic understanding of this disease. In the first funding period, we characterized the key roles of antibodies against these podocyte proteins as disease-causing agents, introduced the first antigen-specific animal models of MN, characterized the molecular architecture of THSD7A in silico, identified the epitopes in THSD7A that are targeted by patient autoantibodies, and defined the landscape of podocyte signalling programs. Despite these advances, the structural and functional consequences of the antigen-antibody interaction remain elusive. Thus, we will pursue the following aims: 1) Characterization of the epitope-specific antigen-antibody interaction and its relation to pathogenicity. 2) Whole-protein structural characterization of the MN antigen THSD7A and high-resolution structural analysis of the immunodominant antibodybinding regions in THSD7A and PLA2R1 by means of cryo-electron microscopy and x-ray crystallography. 3) Investigation of the structure-function relationship between epitopedependent antibody binding and THSD7A-mediated signalling events. Taken together, the analysis of antigen-antibody interaction, high-resolution antigen structure, and epitopedependent signalling programs will lead to a novel molecular understanding of MN and eventually enable novel treatment strategies.

Publications:

  • Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice.

    Nicola M Tomas, Silke Dehde, Catherine Meyer-Schwesinger, Ming Huang, Irm Hermans-Borgmeyer, Johanna Maybaum, Renke Lucas, Jennie L von der Heide, Oliver Kretz, Sarah M S Köllner, Larissa Seifert, Tobias B Huber, Gunther Zahner Kidney int. 2023 Feb

  • The classical pathway triggers pathogenic complement activation in membranous nephropathy.

    Larissa Seifert, Gunther Zahner, Catherine Meyer-Schwesinger, Naemi Hickstein, Silke Dehde, Sonia Wulf, Sarah M S Köllner, Renke Lucas, Dominik Kylies, Sarah Froembling, Stephanie Zielinski, Oliver Kretz, Anna Borodovsky, Sergey Biniaminov, Yanyan Wang, Hong Cheng, Friedrich Koch-Nolte, Peter F Zipfel, Helmut Hopfer, Victor G Puelles, Ulf Panzer, Tobias B Huber, Thorsten Wiech, Nicola M TomasNat Commun. 2023 Jan

  • A slit-diaphragm-associated protein network for dynamic control of renal filtration.

    Maciej K Kocylowski, Hande Aypek, Wolfgang Bildl, Martin Helmstädter, Philipp Trachte, Bernhard Dumoulin, Sina Wittösch, Lukas Kühne, Ute Aukschun, Carolin Teetzen, Oliver Kretz, Botond Gaal, Akos Kulik, Corinne Antignac, Geraldine Mollet, Anna Köttgen, Burulca Göcmen, Jochen Schwenk, Uwe Schulte, Tobias B Huber, Bernd Fakler, Florian Grahammer Nat Commun. 2022 Oct

  • 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

  • Across scales: novel insights into kidney health and disease by structural biology.

    Nicola M Tomas, Simon A Mortensen, Matthias Wilmanns, Tobias B Huber Kidney Int. 2021 Apr

  • Perspectives in membranous nephropathy

    Tomas NM, Huber TB, Hoxha E.  Cell Tissue Res. 2021 Apr

  • Podocytes maintain high basal levels of autophagy independent of mtor signaling.

    Tillmann Bork, Wei Liang, Kosuke Yamahara, Philipp Lee, Zhejia Tian, Shuya Liu, Christoph Schell, Kathrin Thedieck, Bjoern Hartleben, Ketan Patel , Pierre-Louis Tharaux, Olivia Lenoir, Tobias B HuberAutophagy. 2020 Nov

  • A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients

    Meyer-Schwesinger C*, Tomas NM*, Dehde S, Seifert L, Hermans-Borgmeyer I, Wiech T, Koch-Nolte F, Huber TB, Zahner G.Kidney Int. 2020 May* contributed equally

  • A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients.

    Catherine Meyer-Schwesinger, Nicola M Tomas, Silke Dehde, Larissa Seifert, Irm Hermans-Borgmeyer, Thorsten Wiech, Friedrich Koch-Nolte, Tobias B Huber, Gunther ZahnerKidney Int. 2020 May

Project-Team

Project Leaders
Dr. Nicola Tomas
Prof. Dr. Dr. Matthias Wilmanns
Prof. Dr. Tobias B. Huber

Co-Workers
Dr. Ming Huang
Dr. Alice Bochel