18th February - New Publication

Good News! The project B3 headed by Prof. Meyer-Schwesinger will publish two further papers.

A review entitled "The role of the ubiquitin proteasome system in renal physiology and pathophysiology" will appear in Nature Review Nephrology.The paper with the title "Thrombospondin type 1 domain-containing 7A (THSD7A) localizes to the slit diaphragm and stabilized membrane dynamics of fully differentiated podocytes" will be published in JASN.We congratulate all authors.

The role of the ubiquitin proteasome system in renal physiology and pathophysiology
Catherine Meyer-Schwesinger
Nature Review Nephrology, 2019

Intracellular proteins continuously turn over by degradation and synthesis in all organ tissues. Owing to its irreversible nature, protein degradation is a highly selective process to avoid irreparable breakdown of cellular constituents, thereby disrupting cellular stability, integrity and signalling. The majority of intracellular proteins are degraded by the ubiquitin proteasome system (UPS), a multi-enzyme process that involves the covalent conjugation of ubiquitin to a substrate protein and its recognition and degradation by the core multicomponent proteolytic complex of the UPS, the proteasome. In addition to labelling misfolded, damaged, aggregation-prone and intact but unneeded proteins for proteasomal degradation, ubiquitylation regulates a multitude of cellular processes, such as transcription, translation, endocytosis, and receptor activity and subcellular localization. In addition, the proteasome generates peptides for antigen presentation in the immune system and for further degradation by peptidases to provide amino acids for protein biosynthesis and gluconeogenesis. Alterations of the UPS or of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with renal cell dysfunction. In this Review, we provide insight into the elegant and complex nature of UPS-mediated proteostasis, and focus on its established and potential roles in renal cell physiology and pathophysiology.

Thrombospondin type 1 domain-containing 7A (THSD7A) localizes to the slit diaphragm and stabilizes membrane dynamics of fully differentiated podocytes
Johanna Herwig, Sinah Skuza, Wiebke Sachs, Marlies Sachs, Antonio Virgilio Failla, Gabriele Rune, Tobias N. Meyer, Lars Fester, Catherine Meyer-Schwesinger
JASN, 2019

Background: Thrombospondin type 1 domain-containing 7A (THSD7A) has recently been identified as a new podocyte-expressed transmembrane protein, which is targeted by autoimmunity in 3-5% of patients with membranous nephropathy. The temporal and spatial expression of THSD7A and its biological function for podocytes is unknown, even though this knowledge is prerequisite for understanding the effects of THSD7A autoantibodies in MN.
Methods: THSD7A localization was analyzed in postnatal, adult, or autoantibody-injected mice and in human podocytes using high-resolution confocal, SR-SIM, and STED microscopy, as well as immunogold EM. THSD7A function was analyzed in human podocytes by confocal microscopy, Western blotting, adhesion, migration and scratch assays.
Results: THSD7A expression begins upon vascularization with slit diaphragm formation in glomerular development and is lost early upon culture. THSD7A localizes to the basal aspect of foot processes, closely following the meanders of the slit diaphragm in human and mice. Bound autoantibodies to THSD7A localize to the slit diaphragm. In human podocytes, THSD7A expression is accentuated at filopodia and thin arborized protrusions, an expression pattern associated with decreased membrane activity of cytoskeletal regulators. Phenotypically, THSD7A expression in human podocytes does not only increase cell size, enhance adhesion and reduce detachment from collagen-type IV coated plates, but also decreases the ability to migrate.
Conclusion: Our findings suggest that THSD7A functions as a foot process protein involved in the stabilization of the slit diaphragm of mature podocytes and that based on their localization, autoantibodies to THSD7A might structurally and functionally alter the permeability of the slit diaphragm to protein.

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